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One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to "self-medicate" cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-dependent smokers with schizophrenia (n=26) were trained on a cognitive battery and then hospitalized to achieve and maintain confirmed abstinence from smoking for ~1 week. Cognition was tested while smoking as usual (baseline), one day after smoking cessation (early abstinence), ~1 week later (extended abstinence), and within ~3 weeks of resuming smoking (resumption). The test battery included measures of processing speed, attention, conflict resolution, verbal memory, working memory, verbal fluency, and executive function to evaluate multiple cognitive domains affected by schizophrenia. Positive and negative symptoms of schizophrenia, depressive symptoms, and dyskinesia were also measured at baseline and after prolonged abstinence. There were no significant changes in global cognitive test performance with smoking cessation, abstinence, or resumption. There were small decreases in a measure of processing speed and delayed verbal recall with abstinence, but these findings failed to survive adjustments for multiple comparisons. Surprisingly, in this within subject "On-Off-Off-On" design, there were no significant effects of early or prolonged abstinence from smoking on cognitive and behavioral measures in smokers with schizophrenia. The results of this study challenge the widely held "self-medication" hypothesis of smoking and schizophrenia, question the extent of pro-cognitive effects of smoking and nicotine in schizophrenia, and support encouraging smoking cessation in schizophrenia., (Published by Elsevier B.V.)

Background: The uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, induces a range of symptoms resembling those seen in schizophrenia. Enhancement of nicotinic acetylcholine receptor (nAChR) function may have potential as a treatment for the cognitive deficits and negative symptoms of schizophrenia. Accordingly, we examined the modulatory effects of brain nAChR systems on NMDAR antagonist-induced effects., Methods: The interactive effects of ketamine and nicotine were evaluated in 37 healthy subjects in a randomized, placebo-controlled, double-blind, crossover counterbalanced, 2 (intravenous ketamine or placebo) × 2 (intravenous nicotine or placebo) design. Verbal and visual memory, sustained attention, working memory, response inhibition, emotion recognition, executive function, reaction time, motor function, and speed of processing were assessed once per test day, while negative and positive symptoms, perceptual alterations, and a number of feeling states were measured several times before and after administration of drugs., Results: Ketamine induced cognitive deficits and negative and positive symptoms. Nicotine worsened immediate recall, auditory working memory, response inhibition, and executive function and serial processing. Nicotine decreased (improved) reaction time on the sustained attention and choice reaction time tasks. Nicotine did not reduce ketamine-induced cognitive deficits or negative and positive symptoms., Conclusions: At blood levels comparable with tobacco smoking, nicotine infusion does not appear to alleviate the ketamine-induced transient cognitive and behavioral effects in healthy subjects that resemble those seen in schizophrenia. The lack of an effect of nicotine on a spectrum of ketamine effects suggests that the consequences of NMDAR antagonism are not likely under the direct influence of nAChR., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Delta-9-tetrahydrocannabinol (Delta-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Delta-9-THC in humans., Materials and Methods: In a 2-test-day double-blind study, 28 subjects including healthy subjects (n = 17) and frequent users of cannabis (n = 11) were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Delta-9-THC, respectively., Results: Consistent with previous reports, intravenous Delta-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including "high." Delta-9-THC also impaired verbal recall and attention. Haloperidol pretreatment did not reduce any of the behavioral effects of Delta-9-THC. Haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Delta-9-THC. Haloperidol and Delta-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Delta-9-THC induced memory impairments., Conclusions: The deleterious effects of haloperidol pretreatment on the cognitive effects of Delta-9-THC are consistent with the preclinical literature in suggesting crosstalk between DAergic and CBergic systems. However, it is unlikely that DA D(2) receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Delta-9-THC. Further investigation is warranted to understand the basis of the psychotomimetic effects of Delta-9-THC and to better understand the crosstalk between DAergic and CBergic systems.

Background: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders., Methods: In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere., Results: Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation., Conclusions: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

Background and Hypothesis Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study Design We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study Results Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e−7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions Among individuals who regularly use cannabis, genetic liability for schizophrenia—even in those without clinical features—may increase the likelihood of reporting unusual experiences related to cannabis use. [ABSTRACT FROM AUTHOR]

The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis. The objective of the WFSBP task force was to review the literature about this relationship. Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders. Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder. [ABSTRACT FROM AUTHOR]

Objectives: Preclinical and clinical studies suggest that males and females may be differentially affected by cannabis use. This study evaluated the interaction of cannabis use and biological sex on cognition, and the association between observed cognitive deficits and features of cannabis use. Methods: Cognitive measures were assessed in those with regular, ongoing, cannabis use (N = 40; 22 female) and non-using peers (N = 40; 23 female). Intelligence, psychomotor speed, and verbal working memory were measured with the Wechsler Abbreviated Scale of Intelligence, Digit Symbol Test, and Digit Span and Hopkins Verbal Learning Test, respectively. Associations between cognitive measures and cannabis use features (e.g., lifetime cannabis use, age of initiation, time since last use of cannabis, recent high-concentration tetrahydrocannabinoid exposure) were also evaluated. Results: No main effects of group were observed across measures. Significant interactions between group and biological sex were observed on measures of intelligence, psychomotor speed, and verbal learning, with greatest group differences observed between males with and without regular cannabis use. Psychomotor performance was negatively correlated with lifetime cannabis exposure. Female and male cannabis use groups did not differ in features of cannabis use. Conclusions: Findings suggest that biological sex influences the relationship between cannabis and cognition, with males potentially being more vulnerable to the neurocognitive deficits related to cannabis use. [ABSTRACT FROM AUTHOR]

Background: The literature on psychosis-relevant outcomes in cannabis users does not adequately address the confounding effects of other substance use/misuse and psychiatric disorders. Methods: We studied a unique population for whom cannabis use is central and necessary to their way of life. They are forbidden from using other substances, including tobacco and alcohol. Their use of cannabis is heavy, chronic, and begins early. The cases were compared with matched controls who did not use cannabis, alcohol, or drugs. The controls were from the same location and shared similar beliefs and lifestyle, except for cannabis use. Attenuated psychosis-relevant phenomena were assessed with the Schizotypal Personality Questionnaire (SPQ) and cognitive functioning with a culture-neutral computerized cognitive battery. Results: Fifteen cases and 12 matched controls were studied. The cases averaged >30 000 lifetime cannabis exposures. Relative to controls, the cases had significantly higher mean (s.d.) SPQ scores 24 (14.32) v. 13 (8.92), p = 0.031; and poorer cognitive performance, reflected by a lower mean (s.d.) composite cognitive score −0.23 (0.32) v. +0.28 (0.52), p = 0.03. Moderate to large effect sizes were noted for differences in tests of attention, psychomotor speed, working memory, cognitive flexibility, visuo-spatial processing, and verbal memory. A subsample of cases had higher SPQ scores and worse cognitive performance than their siblings not using cannabis. Conclusion: Heavy, chronic, and early cannabis use that is not confounded by other drug use is associated with psychosis-relevant phenomena and cognitive deficits. The findings are relevant to the evolving attitudes and laws about cannabis. [ABSTRACT FROM AUTHOR]

Background Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. Methods In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography and 18 F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory–related activation of a “working memory” circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). Results PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ∼44%, 61%, 76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine-induced effects but did improve working memory accuracy in healthy control subjects. PF-03463275 increased long-term potentiation only in SZs with peak effects at 40 mg twice a day (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated. Conclusions The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating N -methyl-D-aspartate receptor function in the ketamine assay, it enhanced neuroplasticity in SZs. These findings provide support for a clinical trial to test the ability of PF-03463275 to enhance cognitive remediation toward addressing cognitive impairments associated with schizophrenia. [ABSTRACT FROM AUTHOR]

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory 'oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective 'high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing. [ABSTRACT FROM AUTHOR]

The association between cannabis use and psychosis has long been recognized. Recent advances in knowledge about cannabinoid receptor function have renewed interest in this association. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative, and cognitive symptoms in some healthy individuals. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. The mechanisms by which cannabinoids produce transient psychotic symptoms, while unclear may involve dopamine, GABA, and glutamate neurotransmission. However, only a very small proportion of the general population exposed to cannabinoids develop a psychotic illness. It is likely that cannabis exposure is a “component cause” that interacts with other factors to “cause” schizophrenia or a psychotic disorder, but is neither necessary nor sufficient to do so alone. Nevertheless, in the absence of known causes of schizophrenia, the role of component causes remains important and warrants further study. Dose, duration of exposure, and the age of first exposure to cannabinoids may be important factors, and genetic factors that interact with cannabinoid exposure to moderate or amplify the risk of a psychotic disorder are beginning to be elucidated. The mechanisms by which exposure to cannabinoids increase the risk for developing a psychotic disorder are unknown. However, novel hypotheses including the role of cannabinoids on neurodevelopmental processes relevant to psychotic disorders are being studied. [ABSTRACT FROM AUTHOR]

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Δ-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Δ-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Δ-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.Neuropsychopharmacology (2008) 33, 2505–2516; doi:10.1038/sj.npp.1301643; published online 9 January 2008 [ABSTRACT FROM AUTHOR]

Background: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. Methods: In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Δ-9-tetrahydrocannabinol (Δ-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. Results: Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Δ-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. Conclusions: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Δ-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Δ-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia. [Copyright &y& Elsevier]

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (Δ-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. Δ-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that Δ-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders. [ABSTRACT FROM AUTHOR]

N -methyl- d -aspartate glutamate receptor (NMDAR) hypofunction is implicated in the impaired neuroplasticity and cognitive impairments associated with schizophrenia (CIAS). We hypothesized that enhancing NMDAR function by inhibiting the glycine transporter-1 (GLYT1) would improve neuroplasticity and thereby augment benefits of non-pharmacological cognitive training (CT) strategies. This study examined whether co-administration of a GLYT1 inhibitor and computerized CT would have synergistic effects on CIAS. Stable outpatients with schizophrenia participated in this double-blind, placebo-controlled, within-subject, crossover augmentation study. Participants received placebo or GLYT1 inhibitor (PF-03463275) for two 5-week periods separated by 2 weeks of washout. PF-03463275 doses (40 or 60 mg twice daily) were selected to produce high GLYT1 occupancy. To limit pharmacodynamic variability, only cytochrome P450 2D6 extensive metabolizers were included. Medication adherence was confirmed daily. Participants received 4 weeks of CT in each treatment period. Cognitive performance (MATRICS Consensus Cognitive Battery) and psychotic symptoms (Positive and Negative Syndrome Scale) were assessed in each period. 71 participants were randomized. PF-03463275 in combination with CT was feasible, safe, and well-tolerated at the doses prescribed but did not produce greater improvement in CIAS compared to CT alone. PF-03463275 was not associated with improved CT learning parameters. Participation in CT was associated with improvement in MCCB scores. [ABSTRACT FROM AUTHOR]

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any “beneficial” effects of cannabinoid agonists in individuals with schizophrenia—challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT , DAT1 , and AKT1 ) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. [ABSTRACT FROM AUTHOR]