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Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction
Abstract
Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders.
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.
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.
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.
... Urine, blood, oral fluid, and hair can all be tested for cannabinoid metabolites [24] . Among this Urine testing is the commonest, which is generally less expensive, is widely available and as these tests are vulnerable to cheating, the samples are collected under direct observation. ...
... While the subject worns it collects prospective evidence of cannabis compared to the retrospective data collected by other types of testing. The patch should be removed under direct observation and is sent to a laboratory for testing [24] . ...
... Patients testing positive may deny the use and claim the result is a false positive. However, But regardless of the specimen tested (urine, blood, oral fluid, hair, or sweat) clinical laboratories follow certain standard tests that eliminate the possibility of false-positive results [24] . Testing begins with a highly sensitive immunoassay screening test. ...
... Studies using randomized controlled designs have shown, that delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis can induce transient psychotic-like experiences in healthy individuals and worsen existing symptoms in the clinical population (D'Souza et al., 2005). ...
... Furthermore, existing experimental data that has shown that THC further increases psychotic outcomes in clinical populations (D'Souza et al., 2005) aligns with those results of our umbrella review that indicate that adverse effects of cannabis may not be limited to the general population but may further worsen psychosis-related outcomes in clinical populations, especially in patients with established psychosis. This may have important implications for health care professionals working with people at various stages of the psychosis risk and disease continuum with history of co-occurring cannabis use disorder as well as in more general addiction or public health settings. ...
... In randomized controlled trials examining the effects of THC in schizophrenia patients, it was reported that THC led to worsening of positive symptoms, impairment in cognitive functions such as verbal learning and recall, and worsening of negative symptoms (D'Souza et al. 2005). ...
... The first of these is that cannabis causes psychotic disorders on the basis of a genetic predisposition (Kendler et al. 2019). Another explanation is that people with primary psychosis are more susceptible to the biological effects of cannabis (D'Souza et al. 2005). In addition, it is thought that reasons such as impaired cognitive functions, low educational level, impaired social functioning and adverse environmental conditions seen in people with psychotic disorders increase the risk of cannabis use (Kolliakou et al. 2011). ...
Cannabis is known to cause psychotic disorders, and the increasing use of cannabis constitutes an important health problem. Growing evidence that cannabis causes the development of psychosis has led to an increase in the number of studies in this field. This review aims to clarify the role of cannabis use in the development of psychosis, discuss the current literature about the underlying neurobiological mechanisms. For this purpose PubMed was searched for the keywords “cannabis use, psychosis, schizophrenia, endocannabinoid system, pathophysiology, neurobiology”; the articles published in the last 10 years were reviewed. Epidemiological studies showed that cannabis use starting at an earlier age is associated with an increased risk of psychosis, this risk is more pronounced in people with genetic predisposition and increases with heavy and high potency cannabis use. Studies showed that the endocannabinoid system, which plays a role in nervous system development and functions as a homeostatic regulator in physiological processes, is affected by cannabis use during critical periods of development like adolescence; cannabis use affects physiological processes such as synaptic pruning due to the effects of this system on neurotransmitters like glutamate and dopamine leading to long-term behavioral and psychological consequences. Additionally, evidence that dysfunctions in the endocannabinoid system play a role in the etiology of schizophrenia suggests that cannabis affects the disease process by worsening existing dysfunctions in this system. Understanding the relationship between cannabis use and the development of psychosis and underlying neurobiological mechanisms will help to identify new treatment targets, and develop appropriate preventive approaches.
... Seeking short term relief via self-medicating behavior may be risky, since CHR-P individuals who use cannabis may experience transiently increased anxiety and low mood, as well as chronic worsening of depression, interpersonal problems, and difficulty controlling thoughts (Dragt et al., 2012;Peters et al., 2009;Radhakrishnan et al., 2022). Cannabis use can also acutely exacerbate positive symptoms of psychosis (i.e., delusions, hallucinations, and cognitive disorganization) (Bhattacharyya et al., 2015(Bhattacharyya et al., , 2009D'Souza et al., 2005D'Souza et al., , 2004Kleinloog et al., 2012;Liem-Moolenaar et al., 2010;Morgan et al., 2018). A growing body of epidemiological evidence supports linkage between adolescent cannabis use and increased incidence of subsequent chronic psychotic disorder (Andréasson, Engström, Allebeck, & Rydberg, 1987;Arseneault, 2002;Di Forti et al., 2019;Hjorthøj et al., 2023;van Os, 2002). ...
... There is substantial overlap between some of THC's acute adverse effects and psychosis spectrum symptoms, including paranoia, distorted audiovisual and time perception, disorganized cognition, and anxiety. Initial clinical studies demonstrated that intravenously administered THC transiently induces positive and negative symptoms of psychosis in healthy individuals and those with schizophrenia, in a dose-dependent manner (D'Souza et al., 2005(D'Souza et al., , 2004. Many subsequent clinical experiments in healthy adults have replicated these findings with inhaled and oral-use THC (Bhattacharyya et al., 2015(Bhattacharyya et al., , 2009Kleinloog et al., 2012;Liem-Moolenaar et al., 2010;Morgan et al., 2018). ...
Cannabis use is consistently associated with both increased incidence of frank psychotic disorders and acute exacerbations of psychotic symptoms in healthy individuals and people with psychosis spectrum disorders. Although there is uncertainty around causality, cannabis use may be one of a few modifiable risk factors for conversion to psychotic disorders in individuals with Clinical High Risk for Psychosis (CHR-P) syndromes, characterized by functionally impairing and distressing subthreshold psychotic symptoms. To date, few recommendations beyond abstinence to reduce adverse psychiatric events associated with cannabis use have been made. This narrative review synthesizes existing scientific literature on cannabis' acute psychotomimetic effects and epidemiological associations with psychotic disorders in both CHR-P and healthy individuals to bridge the gap between scientific knowledge and practical mental health intervention. There is compelling evidence for cannabis acutely exacerbating psychotic symptoms in CHR-P, but its impact on conversion to psychotic disorder is unclear. Current evidence supports a harm reduction approach in reducing frequency of acute psychotic-like experiences, though whether such interventions decrease CHR-P individuals' risk of conversion to psychotic disorder remains unknown. Specific recommendations include reducing frequency of use, lowering delta-9-tetrahydrocannabinol content in favor of cannabidiol-only products, avoiding products with inconsistent potency like edibles, enhancing patient-provider communication about cannabis use and psychotic-like experiences, and utilizing a collaborative and individualized therapeutic approach. Despite uncertainty surrounding cannabis' causal association with psychotic disorders, cautious attempts to reduce acute psychosis risk may benefit CHR-P individuals uninterested in abstinence. Further research is needed to clarify practices associated with minimization of cannabis-related psychosis risk.
... In other words, cannabinoid exposure may indirectly lead to the vulnerability or causability of future mental disorders, including anxiety disorders. Some of the statistically postulated effects are: impaired short term memory, flawed motor coordination, paranoia, psychosis, poor educational outcomes and lower IQ, just to name a few [8]. Evidently, subjects who suffer these outcomes are at increased risk of anxiety disorders in any of the previously mentioned distinct forms. ...
... In addition to anxiety disorders, other parameters explained by researchers referred to statistically significant susceptibility to commit suicide, depression, and bipolar spectrum disorders, to name a few [7]. Moreover, the hefty use of cannabis can detonate a crisis event in those who already have comorbid mental disorders such as schizophrenia or psychosis [8]. ...
A case-control study in patients diagnosed with anxiety disorders with previous cannabinoid exposure. Community clinic sample population.
... However, it is of note that there is a marked interindividual variability in the susceptibility to cannabis effects, which is thought to have a genetic basis. In this view, individuals who are genetically vulnerable to psychosis show increased cannabis-induced psychotic symptoms (D'Souza et al., 2005;Henquet et al., 2005;Van Os et al., 2002;Verdoux et al., 2003), while a family history of psychosis has also been reported to influence the cannabis use-derived effects on cognitive performance (González-Pinto et al., 2016;Henquet et al., 2006). Based on the demonstrated effect of tetrahydrocannabinol (THC) on central dopaminergic transmission in animal studies (Murray et al., 2007), it is thought that genes influencing the transmission or metabolism of brain dopamine can be involved in such interindividual differences. ...
... Our results are in line with previous studies reporting a dose-response relationship between the frequency of cannabis use and the risk for psychosis (Marconi et al., 2016;Wainberg et al., 2021) and suggest that the individual genetic background could mediate this relationship. In this regard, although this is the first study to assess the interaction between the ZNF804A gene Regarding the relation between the use of cannabis and the ZNF804A gene on the risk for psychosis, there is evidence coming from experimental and longitudinal studies suggesting that cannabis interacts with genetic and environmental liability factors leading to psychotic symptoms (van Os et al., 2002;Verdoux et al., 2003;D'Souza et al., 2005;Henquet et al., 2005;Kahn et al., 2011;Decoster et al., 2012;Radhakrishnan, Wilkinson and D'Souza, 2014;van Winkel and GROUP Investigators, 2015;Wainberg et al., 2021). Nevertheless, it is also well known that there is a genetic background for the likelihood of using cannabis (Kendler et al., 2008) and that this overlaps with the genetic risk of psychotic disorders (Power et al., 2014;Gage et al., 2017;Verweij et al., 2017). ...
According to this, a better understanding of the genetic and environmental influences underlying these disorders may provide a way to dissect the biology of psychosis and, ultimately, allow developing novel therapies. However, the study of the aetiological basis of schizophrenia and other psychotic disorders, though, has a serious limitation in the high biological heterogeneity underlying these pathologies. The heterogeneity of clinical profiles and the high phenotypic variability, in turn, causes uncertainty on the genetic results related to these disorders. Thus, the reduction of phenotypic complexity has become an essential step to contribute to the genetic dissection of brain complex phenotypes.
The present dissertation aimed to contribute disentangling the heterogeneity of
psychotic disorders by means of different approaches: the use of family-based
studies, the use of psychosis-associated intermediate phenotypes and the use of
gene-environment interaction studies. Three specific hypotheses related to these
approaches have been tested, giving rise to six manuscripts submitted to international peer reviewed journals.
The results of the present thesis reveal that the combined use of family-based designs and intermediate phenotypes related to psychosis may facilitate the identification of more homogeneous forms of psychotic disorders in terms of genetic aetiology. Thus, by means of this strategy, two different subclinical phenotypes such as schizotypy (a set of personality traits) and the cognitive dimension of attention and working memory have been identified as familial vulnerability markers for psychosis in samples of families affected with schizophrenia and bipolar disorder, respectively. The study of the familial aggregation pattern of these phenotypes have lead to the identification of subgroups of families with similar phenotypic –and, therefore also genotypic– profiles.
Moreover, by using family-based association designs, different genes involved in the
modulation of synaptic plasticity (DAOA, ZNF804A, AKT1) have been associated with
the risk for psychosis, as measured with the expression of intermediate phenotypes,
including schizotypy and cognitive performance.
Also, results from this thesis provide evidence of the role genetic variability on
cognitive performance and also as a modulator of the effect of cannabis use on the
variance of other intermediate phenotypes. Particularly, it has been revealed the effect of AKT1 gene on attentional processes and, also, the effect of ZNF804A gene on the expression of schizotypy conditional to the cannabis use.
Despite the last advances in the comprehension of the aetiology of psychosis, the
identification of the involved genetic factors has still a long way to go. Thus, it is
necessary to continue making efforts towards understanding the aetiopathogenic
basis of psychotic disorders, taking into account both genetic and environmental
factors. The present dissertation has intended to provide our grain of sand to the
collective construction of knowledge on the aetiology of psychosis by means of using different strategies that have proven to contribute to elucidating the heterogeneity underlying these disorders, which in turn might lead to an improvement of the identification of the underlying causal genetic variants.
http://hdl.handle.net/10803/674023
... People with established psychotic illnesses, such as schizophrenia, have a very high psychotic predisposition and thus are likely to manifest psychotic symptoms when imbibing cannabis. This has been confirmed in people with schizophrenia given intravenous TCH [17]. This is certainly seen clinically, and the negative impact of cannabis on the longitudinal course of schizophrenia is well recognized in longitudinal studies, albeit there is still some debate about the direction of causality and the contribution of confounding factors such as other illicit substances [18]. ...
... What is also of interest is that people with psychotic disorders still remain liable to psychotic relapse upon using cannabis, even if they are taking medications which effectively block dopamine D2 receptors. Indeed, D'Souza and colleagues [17] found that people with schizophrenia were more likely than healthy controls to experience psychotic symptoms when exposed to intravenous THC, even when they were on dopamine antagonist drugs. Thus, the induction of psychotic symptoms by THC is more complex than simply a release of dopamine. ...
The third edition of the textbook presents psychiatry as a medical specialty. The application of science has transformed much of medicine by providing an understanding of the mechanisms of pathology. The genetic basis of psychiatry guarantees a future for explanation by neuroscience. The book sets the scene for such development by explaining the key issues relating to the patient’s perspective, stigma, the global challenge of mental disorder, practical ethics, and the foundations of psychiatry as phenomenology and a medical discipline. It further explains current controversies around diagnosis, psychopathology, evidence, and drug terminology. The scientific basis of psychiatric aetiology and treatment provide simple introductions to the relevant disciplines that underpin our scientific understanding. Individual disorders are covered in sections that follow the structure of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). Thus, it follows a clinically led summary of how patients present with psychiatric disorder. There is no denying the current utility of symptom-based diagnoses and the consensus that created the current categories. However, the project of applying neuroscience to psychiatry has not failed, as has sometimes been implied by criticism of DSM-5. For these reasons, chapters have been included on genetics, neurobiological targets, and imaging in the sections of the book focused on specific disorders. Sections have also been included on service provision and forensic psychiatry because these are critical to the context in which psychiatric disorder is managed.
... Two extensively studied compounds in cannabis are delta-9tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is known for producing psychotomimetic and anxiogenic effects (11,12), whereas CBD is believed to possess antipsychotic, pro-cognitive, and anti-anxiety properties (13,14). These compounds target the endocannabinoid system, which is involved in brain development, cognition, and emotion regulation (14,15). ...
Background
Problematic cannabis use is highly prevalent among people with mood disorders. This underscores the need to understand the effects of cannabis and cannabinoids in this population, especially considering legalization of recreational cannabis use.
Objectives
We aimed to (1) systematically evaluate cross-sectional and longitudinal studies investigating the interplay between cannabis use, cannabis use disorder (CUD), and the occurrence of mood disorders and symptoms, with a focus on major depressive disorder (MDD) and bipolar disorder (BD) and; (2) examine the effects of cannabis on the prognosis and treatment outcomes of MDD and BD.
Methods
Following PRISMA guidelines, we conducted an extensive search for English-language studies investigating the potential impact of cannabis on the development and prognosis of mood disorders published from inception through November 2023, using EMBASE, PsycINFO, PubMed, and MEDLINE databases.
Results
Our literature search identified 3,262 studies, with 78 meeting inclusion criteria. We found that cannabis use is associated with increased depressive and manic symptoms in the general population in addition to an elevated likelihood of developing MDD and BD. Furthermore, we observed that cannabis use is linked to an unfavorable prognosis in both MDD or BD.
Discussion
Our findings suggest that cannabis use may negatively influence the development, course, and prognosis of MDD and BD. Future well-designed studies, considering type, amount, and frequency of cannabis use while addressing confounding factors, are imperative for a comprehensive understanding of this relationship.
Systematic review registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023481634.
... Furthermore, there is clear evidence that psychosisinducing effects of cannabis are further increased by the use of high-potency (skunk) cannabis, i.e. with greater levels of delta9-tetrahydrocannabinol (THC) [17,31,33,34]. Laboratory studies confirmed that administering THC to healthy individuals has proven to induce new onset of transient psychotic symptoms [35][36][37][38]. Besides, THC-users were shown to display more severe positive psychotic symptoms and worse global functioning [39]. ...
Background
Public education efforts to address and reduce potential harms from cannabis use in Arab countries are either slow or inexistent, and do not follow the steadily increasing trends of cannabis use in Arab youth. Several decades of research on substance use, it can be suggested that being aware of, and knowing about, psychosis risk related to cannabis can at least limit the consumption of the substance. Motivated by a lack of measures specifically designed to measure literacy about cannabis-related psychosis risk in younger populations, and based on an extensive literature review, we aimed to create and validate a new self-report scale to assess the construct, the Cannabis-related Psychosis Risk Literacy Scale (CPRL), in the Arabic language.
Method
A cross-sectional study was carried-out during the period from September 2022 to June 2023, enrolling 1855 university students (mean age of 23.26 ± 4.96, 75.6% females) from three Arab countries (Egypt, Kuwait and Tunisia).
Results
Starting from an initial pool of 20 items, both Exploratory Factor Analysis and Confirmatory Factor Analysis suggested that the remaining 8 items loaded into a single factor. The scale demonstrated good internal consistency, with both McDonald omega and Cronbach’s alpha values exceeding 0.7 (omega = 0.85 / alpha = 0.85). The CPRL showed measurement invariance across gender and country at the configural, metric, and scalar levels. Concurrent validity of the CPRL was established by correlations with less favourable attitudes towards cannabis (r = −.14; p <.001). In addition, higher literacy levels were found in students who never used cannabis compared to lifetime users (4.18 ± 1.55 vs. 3.44 ± 1.20, t(1853) = 8.152, p <.001).
Conclusion
The newly developed CPRL scale offers a valid and reliable instrument for assessing and better understanding literacy about cannabis-related psychosis risk among Arabic-speaking young adults. We believe that this new scale is suitable as a screening tool of literacy, as an instrument for measuring the effect of public education interventions aimed at promoting cannabis-related psychosis risk literacy among young people, and as a research tool to facilitate future studies on the topic with a wider application.
... psychoactive ingredient in cannabis, tetrahydrocannabinol (THC), on symptoms among young people with mental illness, current evidence does not support its use (Ahmed et al., 2021;Stanciu et al., 2021). In two laboratory studies, intravenous THC has been shown to increase psychotic symptoms in schizophrenia (D'Souza et al., 2005) but smoked or oral THC did not have this effect among people with schizophrenia and cannabis use disorder (Brunette, 2014). Several observational longitudinal studies have indicated that young people with psychotic disorders who completely stopped using substances had better outcomes than those who continued to use substances (Lambert et al., 2005b;Mullin et al., 2012;Strakowski et al., 2007;Weibell et al., 2017). ...
To inform early intervention, this study describes correlates of substance use among young people with serious mental illness (SMI) enrolled in integrated care in community mental health settings. 227 adults ages 18–35 were assessed for clinical characteristics and substance use. Logistic regressions were used to describe relationships between substance use and participant characteristics. Over a third (38.9%) reported daily cannabis, 15.9% past month other illicit drug, 13.5% frequent/heavy alcohol and 47.4% any of these; 50.2% reported daily tobacco smoking and 23.3% current vaping. Daily cannabis and tobacco were the most common combination. Alcohol, drug, and cannabis with tobacco were associated with higher mental health symptoms but not with emergency room or hospital utilization. Cannabis and other substance use was common and associated with higher symptoms but not with greater hospital utilization, suggesting that early intervention could prevent long-term negative consequences.
... Despite the presence of low physical disability, damage in the cognitive domains, such as mental processing speed, memory, executive function, and attention, can emerge early in the disease and tend to increase over time, resulting in considerable functional impairment [171][172][173]. THC is historically renowned for causing psychotic symptoms and anxiety in healthy people [174], as well as impairing memory [175] and psychomotor function. THC intake is also known to aggravate psychiatric symptoms and raise the likelihood of developing schizophrenia or presenting the illness earlier in the subjects prone to developing it in their lifetime [176]. ...
Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.
... In schizophrenic patients and their healthy siblings, acute administration of the main psychoactive (D'Souza et al.2005, Henquet et al., 2006. D9-THC transiently increases learning deficits, positive and negative symptoms of schizophrenia, perceptual impairments and vigilance deficits (D'Souza et al., 2005). D9-THC acts as an exogenous agonist for endogenous presynaptic cannabinoid receptors. ...
Introduction
Cannabis use impairs cognitive performance in healthy subjects; several studies have shown improved cognitive outcomes in schizophrenic patients using cannabis. The aim of this study was to evaluate the effects of cannabis use on cognitive function in Moroccan patients with schizophrenia who were cannabis users.
Method
Two groups were recruited in a Moroccan University Psychiatric Centre. Fifty patients diagnosed with schizophrenia according to the DSM-V who were cannabis users (SZ CANN +) and forty-nine patients diagnosed with schizophrenia according to DSM-V who do not use cannabis (SZ CANN-). Cognitive functioning was assessed using the CogState neuropsychological battery.
Results
The results of the study suggest that SZ CANN- patients performed better in the test of psychomotor function, attention and verbal memory. While SZ CANN+ patients performed better in the test of working memory, visual memory and emotional recognition. We found no relationship between SZ CANN+ patients and SZ CANN- patients concerning executive function.
Conclusions
Our results suggest that cannabis use may have different effects on neurocognitive functioning. It is associated with disorders of psychomotor function, attention and verbal memory. So, it is associated with an improvement in working memory, visual memory and emotion recognition.
... 9 People with schizophrenia experience adverse clinical effects, like relapse, after using small amounts of drugs of abuse. 10 Thus, it seems that individuals with schizophrenia are more susceptible to the negative effects of psychoactive substances, with even very low levels of alcohol and drug usage having negative effects. ...
... Temporally, cannabis use is associated with younger ages of first psychotic episodes (Large et al., 2011), with severity of cannabis use dose-dependently modulating the risk of developing SZ (Zammit et al., 2002;Henquet et al., 2005), and many patients with cannabis-induced psychosis later develop SZ (Arendt et al., 2005). Importantly, individuals diagnosed with SZ use cannabis at significantly higher rates, with exposure to cannabis transiently exacerbating cognitive and positive symptoms (D'Souza et al., 2005), and a history of cannabis use being associated with worse illness prognosis (Manrique-Garcia et al., 2014;Patel et al., 2020). ...
Background:
Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia.
Methods:
Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals (nine male pairs and one female pair) diagnosed with schizophrenia and non-psychiatric comparisons.
Results:
Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples.
Conclusion:
Given CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.
... 또한, Δ 9 -THC은 향정신성 칸나비노이드로, 대부분의 국가에 서 마약류로 관리되어지고 있으며 해당 성분은 투여 시 일시 적인 불안을 유발하며 (Hindley et al., 2020), 학습능력 및 기억력 저하 (D'Souza et al., 2005), 편집증 및 우울증 (Freeman et al., 2015)을 유발하는 등의 부작용을 나타낸다. 이러한 두 종류의 주된 칸나비노이드의 95% 이상은 식물체 내에서, CBD는 CBDA (cannabidiolic acid), Δ 9 -THC는 Δ 9 -THCA (Δ 9 -tetrahydrocannabinolic acid)의 카르복실기가 결합 되어져 있는 형태로 존재하며 (Tahir et al., 2021), 가열 처리 에 의해 카르복실기가 해리되어 활성을 나타내는 형태로 전환 되어진다 (Ryu et al., 2021). ...
... In contrast to previous findings of an association between cannabis use and diminished expression in SCZ (41), we found no significant associations in BD. The lack of such a relationship in BD could strengthen the hypothesis that the diagnostic groups considered on the more "severe end" of the psychosis spectrum, such as schizophrenia, are more vulnerable to cannabis exposure (76). An extension to this line of reasoning could suggest that cannabis use itself is not a sufficient cause of diminished expression, and that the previously observed association between cannabis use and more severe diminished expression represents cannabis' effect on central pathophysiological mechanisms of SCZ and primary negative symptoms. ...
Background
Negative symptoms are increasingly recognized as transdiagnostic phenomena, linked to reduced quality of life and functioning, and often caused or worsened by amendable external factors such as depression, social deprivation, side-effects of antipsychotics or substance use. The structure of negative symptoms fits into two dimensions: diminished expression and apathy. These may differ in association with external factors that influence their severity and may thus require different treatment approaches. The dimensions are comprehensively established in non-affective psychotic disorders but are understudied in bipolar disorders.
Methods
We conducted exploratory and confirmatory factor analyses in a sample of 584 individuals with bipolar disorder to assess the latent factor structure of negative symptoms as measured by the Positive and Negative Syndrome Scale (PANSS), and performed correlational analyses and multiple hierarchical regression analyses to investigate links between the two dimensions of negative symptoms and clinical and sociodemographic correlates.
Results
The latent factor structure of negative symptoms fits into two dimensions, i.e., diminished expression and apathy. A diagnosis of bipolar type I or a history of psychotic episodes predicted more severe levels of diminished expression. Depressive symptoms were associated with more severe negative symptoms across dimensions, yet 26.3% of euthymic individuals still displayed at least one mild or more severe negative symptom (PANSS score ≥ 3).
Discussion
The two-dimensional structure of negative symptoms seen in non-affective psychotic disorders reproduces in bipolar disorders indicating similarities in their phenomenology. Diminished expression was associated with a history of psychotic episodes and a diagnosis of BD-I, which may infer closer connections to psychosis liability. We found significantly less severe negative symptoms in euthymic than depressed participants. Nevertheless, more than a quarter of the euthymic individuals had at least one mild negative symptom, demonstrating some degree of persistence beyond depressed states.
... Cannabis may induce acute psychotic experiences and also increase the severity of psychotic symptoms. It is also correlated with higher rates of relapse, longer hospitalization time and poorer out-comes [4][5][6][7][8][9][10][11][12]. Many papers have concluded that cannabis abuse is associated with an earlier onset of first-episode psychosis: cannabis users are 2-3 years younger when presenting with the first-episode psychosis than non-users [9,[13][14][15][16][17][18]. ...
Approximately one third of the patients presenting with a first episode psychosis have a history of cannabis use. Some of these patients meet criteria for cannabis induced psychotic disorder (CIPD), which is regarded as a disorder with better outcomes, compared to other psychotic disorders. The aim of this paper was to determine whether there are differences in clinical and demographic features between patients with CIPD and patients with first episode of primary psychotic disorder (PPD) with concurrent cannabis use (CU). A literature search in PubMed database for papers published in English was conducted. A number of 12 studies published between 2002 and 2019 were selected. Available data support the hypothesis that CIPD is a distinct clinical entity from PPD with CU. Differences were found in clinical presentation, as patients with CIPD tend to have a lower intensity of overall psychotic symptoms, a greater insight into psychosis, higher likelihood of visual hallucinations, depersonalization and derealization, and more intense manic symptoms and hostility than patients with PPD with CU, and in family history, as patients with CIPD are more likely to have a close relative that meets criteria for substance use disorder, but less likely to have a close relative diagnosed with psychotic disorder. However, a significant percentage (25-45%) of patients initially treated for CIPD will meet criteria for a chronic psychotic disorder in the following years and continuous cannabis use is associated with poor prognosis, independent of the initial diagnosis. In these conditions, early intervention is crucial and substance use treatment should be considered a priority in cannabis users that develop psychotic symptoms.
... Studies using randomized controlled designs have shown, that delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis can induce transient psychotic-like experiences in healthy individuals and worsen existing symptoms in the clinical population (D'Souza et al., 2005). Crosssectional studies have shown that cannabis use is more frequent in individuals at clinical high-risk of psychosis (CHR) and those with established psychosis than in healthy controls (Addington et al., 2014;Pardo et al., 2021). ...
While the legal status and public perception of cannabis are currently changing in many countries, one of the important considerations from a public health viewpoint is its potential association with adverse health outcomes such as the development of psychosis. This has not only led to an increasing number of systematic reviews and meta-analyses that have been published on this topic but also to aconcomitant increase in conflicting results which complicates evidence-based decision-making. Toaddress this issue, we conducted an umbrella review of systematic reviews and meta-analyses using the AMSTAR-2 to assess the quality of included reviews. We further created an evidence map to visualize and facilitate the overview of the published evidence synthesis on the association between cannabis use and all psychosis-related outcomes and risk moderators in healthy, high-risk, and clinical populations. Overall, we found 32 systematic reviews and meta-analyses. Based on a synthesis of current evidence, cannabis use is associated with subclinical psychosis states (psychotic-like experiences) and traits (schizotypal personality) in the healthy population, as well as earlier onset and development of psychosis. The effects of cannabis use in the clinical high-risk population remainunclear, however, its effects in those with established psychosis seem robust in terms of an increased risk of relapse. A dose-response effect and an increased risk of clinically relevant adverse outcomes with earlier cannabis use in adolescents, frequency of use and potentially, potency of cannabis usedhave also been consistently shown across the psychosis continuum. The existence of childhood trauma may further increase the risk of development of psychosis, while single nucleotide polymorphisms such as on the AKT1-gene, DRD2-gene, CHRM3-gene and PRX- gene may serve as genetic moderators. Genetic mendelian randomization studies further implicate a bi-directional association between cannabis use and psychosis, however, further research using polygenetic risk scores and epigenetic analyses is warranted. It currently remains unclear whether concurrent substance use in combination with cannabis use may further potentiate the risk of adverse psychosis outcomes. A critical and systematic synthesis of extant evidence provided here may help highlight areas where there is optimal evidence as well as identify gaps in evidence and inform decision-making with clinical and public health implication
... The strongest evidence is for cannabis and amphetamine-type stimulants in relation to their effect on the development of psychosis [6,21,22], but psychotic symptoms are also commonly associated with cocaine and hallucinogen use [6,23]. These drugs may induce acute psychosis [22] or exacerbate psychotic episodes in patients with SSD [24]. ...
Objectives:
Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use.
Methods:
The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20-29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score.
Results:
At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients.
Conclusion:
The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.
... Furthermore, the severity of cannabis use's effects on patients with schizophrenia relative to other comorbid SUDs makes cannabis use even more interesting to clinicians and researchers alike. The exact neurobiological interactions between cannabis and schizophrenia are not well understood; however, the effects of cannabis on chemical pathways in the brain suggest a connection via neurotransmitter manipulation (Burns, 2013;D'Souza et al., 2005;Jager et al., 2010;Shrivastava et al., 2014;Solowij & Michie, 2007). Concerning the causes of cannabis use, Khantzian's self-medication hypothesis (discussed later) is most relevant. ...
Within the past two decades, psychiatric clinics have seen an increase in the number of patients with schizophrenia who use cannabis. Studies have demonstrated the drug’s exacerbating effects on schizophrenia symptoms and treatment, posing a challenge to clinicians who treat this patient population. However, insight into the perspectives and needs of these clinicians remains largely absent within the existing literature. To provide them a voice, this study utilized surveying and interviewing with a mixed quantitative and qualitative design to evaluate and analyze the perspectives, concerns, and needs of clinicians who treat patients with schizophrenia who use cannabis. Participating clinicians (n = 5) were generally confident in understanding how cannabis use affects schizophrenia and their roles as providers. However, these clinicians were less confident in the effectiveness of existing treatments, education, and literature on the subject. Additionally, participants voiced concerns about issues such as the limitations of existing literature on this patient population, the lack of established guidelines and protocols for treating this patient population, and the absence of educational resources and materials for both clinicians and patients. Overall, the number of voiced concerns and the high variation between clinicians strongly imply the necessity of these clinicians’ perspectives within research on this patient population. Increased involvement of medical professionals within the literature on cannabis use in schizophrenia should hopefully serve to implement and improve the resources that these clinicians need to make a lasting positive change in patients with schizophrenia who use cannabis.
... Although the mechanisms are not fully understood, pharmacological and brain imaging studies suggest that psychotic and manic symptoms are partly due to dopaminergic hyperactivity. THC from cannabis binds to endocannabinoid receptors leading to a signaling cascade that decreases dopamine reuptake, which may promote dopaminergic activity and, consequently, exacerbate symptoms [27,30,31]. ...
Cannabis use disorder (CUD) is a complex issue, even more so when it is comorbid with a severe mental disorder (SMD). Available interventions are at best slightly effective, and their effects are not maintained over time. Therefore, the integration of virtual reality (VR) may increase efficacy; however, it has not yet been investigated in the treatment of CUD. A novel approach, avatar intervention for CUD, uses existing therapeutic techniques from other recommended therapies (e.g., cognitive behavioral methods, motivational interviewing) and allows participants to practice them in real-time. During immersive sessions, participants are invited to interact with an avatar representing a significant person related to their drug use. This pilot clinical trial aimed to evaluate the short-term efficacity of avatar intervention for CUD on 19 participants with a dual diagnosis of SMD and CUD. Results showed a significant moderate reduction in the quantity of cannabis use (Cohen’s d = 0.0.611, p = 0.004), which was confirmed via urinary quantification of cannabis use. Overall, this unique intervention shows promising results. Longer-term results, as well as comparison with classical interventions in a larger sample, are warranted through a future single-blind randomized controlled trial.
... 116 There is evidence to suggest a positive association between cannabis use and development of psychosis, in people susceptible to psychotic disorders. [117][118][119] Although no definitive causal effects have been established, there are case reports of stroke, acute coronary syndrome, and cardiac arrhythmias associated with use of cannabis. 120,121 Maternal exposure to cannabis can adversely affect conception and/or maintenance of pregnancy. ...
Background: One in five individuals live with chronic pain globally, which often co-occurs with sleep problems, anxiety, depression, and substance use disorders. Although these conditions are commonly managed with cannabinoid-based medicines (CBM), health care providers report lack of information on the risks, benefits, and appropriate use of CBM for therapeutic purposes. Aims: We present these clinical practice guidelines to help clinicians and patients navigate appropriate CBM use in the management of chronic pain and co-occurring conditions. Materials and Methods: We conducted a systematic review of studies investigating the use of CBM for the treatment of chronic pain. Articles were dually reviewed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Clinical recommendations were developed based on available evidence from the review. Values and preferences and practical tips have also been provided to support clinical application. The GRADE system was used to rate the strength of recommendations and quality of evidence. Results: From our literature search, 70 articles met inclusion criteria and were utilized in guideline development, including 19 systematic reviews and 51 original research studies. Research typically demonstrates moderate benefit of CBM in chronic pain management. There is also evidence for efficacy of CBM in the management of comorbidities, including sleep problems, anxiety, appetite suppression, and for managing symptoms in some chronic conditions associated with pain including HIV, multiple sclerosis, fibromyalgia, and arthritis. Conclusions: All patients considering CBM should be educated on risks and adverse events. Patients and clinicians should work collaboratively to identify appropriate dosing, titration, and administration routes for each individual. Systematic Review Registration: PROSPERO no. 135886.
... [10][11][12] Despite a drop in the perceived harm of cannabis use, as well as its increased acceptability in the last decades, several undesirable health sequelae, including exacerbated psychiatric symptoms (i.e., psychotic symptoms), worse prognosis, increased hospitalization, higher risk of suicidal behaviors, and decreased quality of life, have been linked to cannabis use, mainly its heavy and persistent use. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Notwithstanding advances in knowledge on the association between cannabis use and violence in the general population, limited consideration has been dedicated to those with SMD. [33][34][35][36][37][38][39][40][41][42] Unlike studies of other substances, the cannabis-violence relationship remains a topic of debate. ...
Introduction: Recent longitudinal studies point toward the existence of a positive relationship between cannabis use and violence in people with severe mental disorders (SMD). However, the existence of a dose-response relationship between the frequency/severity of cannabis use and violence has seldom been investigated. Therefore, this study aims to determine if such a relationship exists in a psychiatric population. Methods: To do so, a total of 98 outpatients (81 males and 17 females, all over 18 years of age) with SMD were recruited at the Institut universitaire de santé mentale de Montréal (Montréal, Canada) and included in the analyses. Clinical evaluations were conducted every 3 months for a year. Substance use, violent behaviors, and potential covariables were assessed through self-reported assessments, urinary testing, as well as clinical, criminal, and police records. Using generalized estimating equations, the association between cannabis use frequency (nonusers, occasional, regular, and frequent users) and violence was investigated, as well as the association between the severity of cannabis use and violent behaviors. Results: It was found that cannabis use frequency and severity were significant predictors of violent behaviors. After adjustment for time, age, sex, ethnicity, diagnoses, impulsivity, and use of alcohol and stimulants, odds ratios were of 1.91 (p<0.001) between each frequency profile and 1.040 (p<0.001) for each increase of one point of the severity of cannabis use score (ranging from 0 to 79). Conclusions: Despite the high attrition rate, these findings may have important implications for clinicians as cannabis use may have serious consequences in psychiatric populations. Nevertheless, the mechanisms underlying this association remain unclear.
... Others have argued that cannabis exposure is linked to schizophrenia in that it may commence during the premorbid phase of schizophrenia (D'Souza et al., 2005) and represent a form of self-medication while "feeling off" during this premorbid phase. According to D' Souza et al. (2005), individuals experiencing premorbid schizophrenia may use cannabis to alleviate symptoms. ...
The effects of cannabis use on the brain, mind, and body have been studied for decades. The developing brain, particularly the adolescent and young adult brain, undergoes critical development that makes it especially susceptible to the effects of cannabis use. Among the adverse effects of cannabis use in adolescence and young adulthood, psychosis and psychotic disorders (e.g., schizophrenia) have been examined. The association of cannabis use with schizophrenia was first elucidated in a Swedish study of army conscripts. Specifically, conscripts reported their cannabis use exposure and were followed longitudinally to assess the emergence of schizophrenia. The authors found that those who reported persistent cannabis use during adolescence had higher rates of schizophrenia diagnoses.\r Notwithstanding this correlation, a causal relationship has not yet been established between adolescent cannabis use and schizophrenia. Some believe that in the premorbid phase of schizophrenia, one may self-medicate with cannabis, accounting for the correlational relationship. However, this evidence is not supported by the literature. Prolonged, frequent use of exogenous cannabinoids such as phytocannabinoids and synthetic cannabinoids perturb the endocannabinoid system, particularly during the critical period of adolescence. Many researchers believe this perturbation contributes to psychosis and the pathogenesis of schizophrenia. In this review, I demonstrate how cannabis may contribute to symptoms of psychosis and associated with diagnoses of schizophrenia. PubMed and Google Scholar were used with the following search terms "cannabis-induced psychosis" AND schizophrenia. These search terms were narrowed by clicking on "adolescent." Also, based on the diathesis-stress model, I explored how cannabis may be one of many neurological insults leading to the onset of schizophrenia. In the future, research should be conducted focusing on other drugs as a trigger for schizophrenia.
... According to previous studies, higher levels of basal NS in patients with FEP, appear to be related to the following factors: male gender, younger age at onset of psychosis (Ballageer et al., 2005;Dominguez et al., 2010;Drake et al., 2016;Üçok and Ergül, 2014), worse basal functioning (Álvarez-Jiménez et al., 2012;Chang et al., 2016;Strauss et al., 2012), poor functional outcome at follow-up (Browne et al., 1996;Ho et al., 1998;Malla et al., 2002), and longer duration of untreated psychosis (DUP) (Boonstra et al., 2012;Edwards et al., 1999;Larsen et al., 1996;Malla et al., 2002). Other studies have observed an association between cannabis abuse and lower NS levels at the onset of FEP (D'Souza et al., 2005;Green et al., 1999;Rammou et al., 2017;Talamo et al., 2006). ...
Introduction:
Negative symptoms are nuclear features of schizophrenia that may be present from the onset of the disease. In recent years, it has been described 2 subdomains of negative symptoms: experiential and expressive deficits. The aim of the study is to examine the relationship between negative symptoms and demographic and clinical variables in patients with first-episode psychosis. Also, to explore whether there are differences in the association among these variables and negative symptoms when divided into both subdomains.
Material and methods:
A cross-sectional study was performed in 160 patients (52 females and 108 males) with a diagnosis of a first episode psychosis. A questionnaire was administered to collect demographic and clinical variables.
Results:
A backward stepwise linear regressions analysis was performed in order to observe potential associations between demographic and clinical variables and the presence of negative symptoms. All three models are predicted by worse PSP score, a higher CDSS, a higher disorganized factor score and a lower excited factor score. A longer duration of untreated psychosis (DUP) is associated to a higher score in the experiential deficit subdomain only.
Conclusions:
Our work highlights some clinical and phenomenological differences between experiential and expressive deficits. We think that taking into account both subdomains in future studies may lead to more accurate clinical assessment and interventions.
... We additionally categorised clinically significant psychotic-like reactions as increases in PANSS scores from baseline of ≥3 points, as in previous studies due to floor effects [27,28]. Similarly, we categorised any increase in SSPS score from baseline. ...
As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = −4.709, d = 0.69, p = 2.41 × 10–5). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis.
... We do not know why he responded in a paradox manner to the applied benzodiazepines but could be ± at least for a time ± sedated by dronabinol. Due to its adverse effects on psychotic symptoms and on cognition, dronabinol is usually contraindicated in schizophrenia [6]; however, for cycloid psychoses different pathophysiologic mechanisms can be postulated, thus different psychopharmacological approaches might be tried. ...
... The above studies on NRG1/ErbB4 regulation of LTP mainly focused on PV-positive interneurons, however, the effect of NRG1/ErbB4 signaling on other types of interneurons remain largely elucidated. Endocannabinoids (eCBs) are implicated in the regulation of synaptic plasticity, cognition, and emotion (Castillo et al., 2012;Zanettini et al., 2011); eCBs system dysfunction is involved in schizophrenia (D'Souza et al., 2005;Giuffrida et al., 2004). The type 1 cannabinoid receptor (CB1R) is expressed in Cholecystokinin (CCK)-, but not PV-positive interneurons, suggesting an unique function of eCBs signaling in CCK-positive interneurons. ...
Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.
... Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes (Grech et al., 2005;Jenkins and Khokhar, 2021). While there are studies showing acute THC administration to schizophrenia patients can aggravate the disease symptoms including cognitive functions (D'Souza et al., 2005), CBD, the other psychoactive component in cannabis shows antipsychotic properties (Batalla et al., 2019). On the other hand, chronic cannabis users with schizophrenia have been found to have superior cognitive functioning compared to non-users, at least in certain subgroups of patients (Jockers-Scherübl et al., 2007). ...
The consequences of cannabis use, especially in the context of schizophrenia, have gained increased importance with the legalization of cannabis in North America and across the globe. Cannabis use has multifaceted impacts on cognition in schizophrenia patients and healthy subjects. Healthy subjects, particularly those who initiated cannabis use at earlier ages and used high-potency cannabis for longer durations, exhibited poorer cognition mainly in working memory and attention. Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes. However, cannabis-using patients have better overall cognitive performance compared to patients who were not cannabis users. Interestingly, these effects were only apparent in lifetime cannabis users, but not in current (or within last 6 months) users. Moreover, higher frequency and earlier age of cannabis use initiation (i.e., before 17 years of age) were associated with better cognitive performance, although they had an earlier illness onset. Three possible hypotheses seem to come forward to explain this paradox. First, some components of cannabis may have antipsychotic or cognitive-enhancing properties. Secondly, chronic cannabis use may alter endocannabinoid signaling in the brain which could be a protective factor for developing psychosis or cognitive impairments. A third explanation could be their representation of a phenotypically distinct patient group with more intact cognitive functioning and less neurodevelopmental pathology. Multiple factors need to be considered to understand the complex relationship between cannabis, cognitive function, and schizophrenia. In short, age at initiation, duration and rate of cannabis use, abstinence duration, co-use of substances and alcohol, prescribed medications, relative cannabinoid composition and potency of cannabis, presence of genetic and environmental vulnerability factors are prominent contributors to the variability in outcomes. Animal studies support the disruptive effects of Δ9-tetrahydrocannabinol (THC) administration during adolescence on attention and memory performance. They provide insights about interaction of cannabinoid receptors with other neurotransmitter systems, such as GABA and glutamate, and other regulatory molecules, such as PSD95 and synaptophysin. Cannabidiol (CBD), on the other hand, can improve cognitive deficits seen in neurodevelopmental and chemically-induced animal models of schizophrenia. Future studies focusing on bridging the translational gaps between human and animal studies, through the use of translationally relevant methods of exposure (e.g., vaping), consistent behavioral assessments, and congruent circuit interrogations (e.g., imaging) will help to further clarify this complex picture.
Cannabis, one of the most widely used psychoactive substances worldwide, can give rise to acute cannabis-associated psychotic symptoms (CAPS). While distinct study designs have been used to examine CAPS, an overarching synthesis of the existing findings has not yet been carried forward. To that end, we quantitatively pooled the evidence on rates and predictors of CAPS ( k = 162 studies, n = 210,283 cannabis-exposed individuals) as studied in (1) observational research, (2) experimental tetrahydrocannabinol (THC) studies, and (3) medicinal cannabis research. We found that rates of CAPS varied substantially across the study designs, given the high rates reported by observational and experimental research (19% and 21%, respectively) but not medicinal cannabis studies (2%). CAPS was predicted by THC administration (for example, single dose, Cohen’s d = 0.7), mental health liabilities (for example, bipolar disorder, d = 0.8), dopamine activity ( d = 0.4), younger age ( d = −0.2), and female gender ( d = −0.09). Neither candidate genes (for example, COMT , AKT1 ) nor other demographic variables (for example, education) predicted CAPS in meta-analytical models. The results reinforce the need to more closely monitor adverse cannabis-related outcomes in vulnerable individuals as these individuals may benefit most from harm-reduction efforts.
Schizophrenia is a serious mental health disorder that confers one of the highest mortality rates of all psychiatric illnesses. Although the disorder’s psychotic symptoms are treatable with conventional antipsychotics, they remain incurable. Moreover, medication adherence is poor, and individuals with schizophrenia choose to self-medicate with illicit substances, including cannabis. It is well-established that the delta-9-tetrahydrocannabinol (delta-9-THC) component of cannabis elicits psychotomimetic effects at high doses; worsens schizophrenia-related psychosis; commonly develops into cannabis use disorder in individuals with schizophrenia; and increases the risk of earlier-onset schizophrenia symptoms in those harboring genetic susceptibility. However, individuals with schizophrenia commonly use cannabis and cannabis derivatives such as cannabidiol (CBD). These products seem to alleviate psychotic symptoms and relieve adverse side effects of antipsychotic medications. Therefore, one notion that has gained traction is the potential utility of cannabis-derived cannabidiol (CBD) as adjunct treatment to reduce schizophrenia-associated psychosis and other symptoms. Currently, preclinical and clinical data remain inconclusive. The present review distinguishes the mechanisms underlying schizophrenia-associated vs. cannabis-induced psychosis; reviews the evidence for delta-9-THC-mediated exacerbation vs. CBD-mediated amelioration of schizophrenia-associated psychosis; and describes potential approaches for incorporating CBD into schizophrenia therapeutic regimen in a safe and efficacious manner.
Cannabis use has been stated as a causal risk factor for the occurrence of schizophrenia and other psychotic disorders. There is a dearth of literature stating the association of cannabis with bipolar disorder. This review aimed to find the repercussion of cannabis use on the onset of the first episode of bipolar disorder and the worsening of the symptoms in pre-existing illness. A thorough systematic review of the existing literature was carried out using the PRISMA guidelines. PubMed, Medline, EMBASE, SCOPUS, and Google-scholar databases were searched for studies fitting our study’s inclusion and exclusion criteria. A total of 25 studies were included in the systematic review and out of these 25 studies, five prospective studies met the inclusion criteria for the primary outcome meta-analysis. A total sample of 13,624 individuals was included in these five studies. A fixed effect model was used in the meta-analysis of these five studies and it revealed an association between cannabis and bipolar disorder with an effect size of 2.63 (95% CI: 1.95–3.53) (heterogeneity: chi² = 3.01, df = 3 ( P = 0.39); I² = 0%). Our findings propose that cannabis use may precipitate or worsen bipolar disorder. This highlights the importance of the detrimental effect of cannabis use on bipolar disorder and the need to discourage cannabis use in the youth culture. High-quality prospective studies are required to delineate the effect of cannabis use on bipolar disorder.
Mounting evidence suggests safety and tolerability of cannabis-derived and psychedelic drugs as potential novel therapeutics for psychiatric, as well as sleep and pain disorders. Evidence concerning the therapeutic efficacy of these compounds remains controversial, although some promising preliminary results are available for them in specific disorders. For example, CBD is approved as medication for treatment-refractory epilepsy, while MDMA and psilocybin are being tested in phase 3 clinical trials respectively for treatment-refractory PTSD and MDD. Despite encouraging preliminary results, further preclinical and clinical trials are required to validate these findings. Most importantly, more systematic research is required to assess the potential long-term side effects that might arise following the use of cannabinoids and psychedelic compounds in psychiatric settings.
The impact of cannabis use on neurological soft signs (NSS) in patients with schizophrenia is a topic of growing interest. This narrative review aims to provide an overview of the current understanding of this relationship. The PubMed database was used to identify relevant articles, and the initial search yielded a total of 144 publications. By using automation tools, 137 records were removed, and seven remaining studies were further reviewed in full-text. Results. The findings suggest that, although the use of cannabis decreases the global expression of NSS, heavy cannabis use is associated with higher levels of NSS in sensorimotor subdomains related to complex motor tasks. Furthermore, neuroimaging studies have revealed alterations in brain regions involved in sensorimotor execution and control in individuals with heavy cannabis use. These findings support the hypothesis that cannabis, through its effects on the sensorimotor system, can impair neurological functioning and increase the positive symptoms of schizophrenia. In conclusion, this narrative review highlights the complex relationship between cannabis use, neurological soft signs and schizophrenia. Understanding the impact of cannabis on NSS in patients with schizophrenia is crucial for developing targeted interventions and for optimizing treatment outcomes. Further research, including longitudinal studies and meta-analyses, is warranted to enhance our understanding of this important area.
Brain development is a complex phenomenon from fetal life to adolescence. During this period, the brain’s maturation proceeds through a series of ordered events, including critical periods of plasticity. The brain is particularly sensitive to the environment during the changes. The endocannabinoid system participates directly and indirectly in the plasticity and maturation processes. The main psychoactive component of Cannabis, delta-9-tetrahydrocannabinol, can cross the placental barrier; it is present in breast milk and diffuses in the brain; it interacts with endocannabinoid signaling, especially through activating cannabinoid receptors which can lead to abnormal neurodevelopmental processes and the functions of neuronal circuits [1].
Background
The diathesis-stress paradigm and the cannabinoid-hypothesis have been proposed as possible pathophysiological models of schizophrenia. However, they have historically been studied independently of each other.
Objective
This PRISMA 2020-compliant systematic review aimed at reappraising the interplay be- tween the hypothalamic-pituitary-adrenal (HPA) axis and the endocannabinoid (eCB) system in psy- chosis-spectrum disorder risk and outcome.
Methods
All pathophysiological and outcome clinical studies, concomitantly evaluating the two sys- tems in psychosis-spectrum disorder risk and different stages of illness, were gathered from electronic databases (Pubmed, Web of Science, and Scopus), and discussed.
Results
41 eligible outputs were extracted, focusing on at least a biological measure (9 HPA-related studies: 4 eCB-interventional, 1 HPA-interventional, 1 both HPA-interventional and non-interventional, 3 non-interventional; 2 eCB-related studies: non-interventional), environmental measures only (29 studies: 1 eCB- interventional, 28 non-interventional), and genetic measures (1 study: non-interventional). In- dependent contributions of aberrancies in the two systems to the physiopathology and outcome of psy- chosis were confirmed. Also, concomitant alterations in the two systems, either genetically defined (e.g., CNR1 genetic variation), biologically determined (e.g., dysfunctional HPA axis or endocanna- binoid signaling), or behaviorally imputed (e.g., cannabis use, stress exposure, and response), were consistently reported in psychosis. Further, a complex biobehavioral perturbation was revealed not on- ly within each system (e.g., cannabis use affecting the eCB tone, stress exposure affecting the HPA ax- is), but also across the two systems (e.g., THC affecting the HPA axis, childhood trauma affecting the endocannabinoid signaling).
Conclusion
There is a need to concomitantly study the two systems’ mechanistic contribution to psychosis in order to establish more refined biological relevance.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.
Alterations in cannabinoid CB1 receptor (CB1R) are implicated in various psychiatric disorders. CB1R participates in both depolarization induced suppression of inhibition (DSI) and depolarization induced suppression of excitation (DSE), suggesting its involvement in regulating excitatory and inhibitory (E/I) balance. Prior studies examining neuronal cell type specific CB1R distribution have been conducted near exclusively within rodents. Identification of these distribution patterns within the human and non-human primate cortex is essential to increase our insight into its function. Using co-labeling immunohistochemistry and fluorescent microscopy, we examined CB1R protein levels within excitatory and inhibitory boutons of human and non-human primate prefrontal cortex and auditory cortices, regions involved in the behavioral effects of exogenous cannabinoid exposures. We found that CB1R was present in both bouton populations within all brain regions examined in both species. Significantly higher CB1R levels were found within inhibitory than within excitatory boutons across all regions in both species, although the cell type by brain region interactions differed between the two species. Our results support the importance of conducting more in-depth CB1R examinations to understand how cell type and brain region dependent differences contribute to regional E/I balance regulation, and how aberrations in CB1R distribution may contribute to pathology.
The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABA A receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212–2 (EC 50 of 138 n m ). This effect was blocked by the CB1 receptor antagonist SR141716A (1 μ m ) but not by the opioid antagonist naloxone. In contrast, evoked GABA B -mediated IPSCs were insensitive to the CB agonist. WIN 55,212–2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212–2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212–2. The presynaptic effect of WIN 55,212–2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212–2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABA A - but not GABA B -mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids 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 may affect memory, cognition, and pain perception by means of this cellular mechanism.
Dear Collague,
please note that the requested paper is a book - and due to copyright protection, I cannot send you this book. But there are lots of papers on this topic, including a 50 pages long review paper. Just drop me a mail on my regular email account
ebrunne1@gwdg.de
- and I can send you the following articles/papers:
Brunner, E. and Langer, F. (2000). Nonparametric Analysis of Ordered Categorical Data in Designs with Longitudinal Observations and Small Sample Sizes. Biometrical Journal 42, 663-675.
Brunner, E. and Puri, M.L. (2001). Nonparametric Methods in Factorial Designs. Statistical Papers 42, 1-52.
Brunner, E. and Puri, M.L. (2001). Point and interval estimators for nonparametric treatment effects in designs with repeated measures. In: Data Analysis from Statistical Foundations: Festschrift in Honor of Donald A.S. Fraser. (Editor: A.K.E. Saleh) Nova Science Publishers, Inc., New York, 167–178.
Konietschke, F., Bathke, A.C., Hothorn, L.A., and Brunner, E. (2010). Testing and Estimation of purely nonparametric effects in repeated measures designs. Computational Statistics & Data Analysis 53, 730-741.
Noguchi, K., Gel, Y., Brunner, E. , Konietschke, F. (2012). nparLD: An R Software Package for the Nonparametric Analysis of Longitudinal Data in Factorial Experiments. Journal of Statistical Software 50, Iss. 12.
Kind regards,
Edgar Brunner
A new test of verbal learning and memory, the Hopkins Verbal Learning Test, was developed. The test consists of three trials of free-recall of a 12-item, semantically categorized list, followed by yes/no recognition. Six parallel forms yielded equivalent results in normals. The performance of patients with Alzheimer's disease and chronic amnesia is described. The test is likely to be useful in patients too impaired for more comprehensive memory assessments and where repeated testing is necessary.
Positron emission tomography (PET) was used to inves-tigate the hypothesis that older adults' difficulties with temporal-order memory are related to deficits in frontal function. Young (mean 24.7 years) and old (mean 68.6 years) participants studied a list of words, and were then scanned while retrieving information about what words were in the list (item retrieval) or when they occurred within the list (temporal-order retrieval). There were three main results. First, whereas the younger adults engaged right prefrontal regions more during temporal-order retrieval than during item retrieval, the older adults did not. This result is consistent with the hypothesis that context memory deficits in older adults are due to frontal dysfunction. Second, ventromedial temporal activity during item memory was relatively unaffected by aging. This finding concurs with evidence that item memory is relatively preserved in old adults and with the notion that medial temporal regions are involved in automatic retrieval operations. Finally, replicating the result of a previous study (Cabeza,, the old adults showed weaker activations than the young adults in the right prefrontal cortex but stronger activations in the left prefrontal cortex. The age-related increase in left prefrontal activity may be interpreted as compensatory. Taken together, the results suggest that age-related changes in brain activity are rather process-and region-specific, and that they involve increases as well as decreases in neural activity. &
The purpose of this study was to develop an instrument for the measurement of present-state dissociative symptoms, the Clinician Administered Dissociative States Scale (CADSS). Reported here are interrater reliability and internal consistency of the CADSS, validity as assessed by comparisons with other instruments for the assessment of dissociation, and sensitivity of the CADSS to discriminate patients with dissociative disorders from patients with other psychiatric disorders and healthy subjects. Initial analyses indicated good interrater reliability and construct validity for the CADSS. Scores on the CADSS discriminated patients with dissociative disorders from the other groups.
The exposure of pregnant rats to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of Cannabis sativa, during the perinatal period affects the gene expression and the activity of tyrosine hydroxylase (TH) in the brains of their offspring at peripubertal and adult ages. In the present work we explored whether these effects also appear during fetal and early neonatal periods, when TH expression plays an important role in neural development. To this end, the mRNA amounts for TH and the amounts and activity of this enzyme, in addition to catecholamine (CA) contents, were analyzed in the brain of fetuses at different gestational days (GD) and of newborns at two postnatal ages, which had been daily exposed to Δ9-THC or vehicle from d 5 of gestation. Results were as follows. The exposure to Δ9-THC markedly affected the expression of the TH gene in the brain of fetuses at GD 14. Thus, the amounts of its mRNA at this age were higher in Δ9-THC-exposed fetuses than in controls. This corresponded with a marked rise in the amounts of TH protein and in the activity of this enzyme at this age. Normalization was found in these parameters at GD16. However, a marked sexual dimorphism in the response of TH gene to cannabinoid exposure appeared from GD18 and was particularly evident at GD21, when TH-mRNA amounts increased in developing female brains, but decreased in developing male brains exposed to Δ9-THC, effects that were mostly prolonged to early postnatal ages. However, these changes did not correspond always with parallel changes in the amounts and activity of TH and in CA contents, as occurred in GD14, suggesting that Δ9-THC would not be affecting the basal capability to synthesize CAs in TH-containing neurons,. Copyright © 1996 Humana Press Inc. All rights of any nature whatsoever reserved.
In the first decade of neurocognitive word production research the predominant approach was brain mapping, i.e., investigating the regional cerebral brain activation patterns correlated with word production tasks, such as picture naming and word generation. Indefrey and Levelt (2004) conducted a comprehensive meta-analysis of word production studies that used this approach and combined the resulting spatial information on neural correlates of component processes of word production with information on the time course of word production provided by behavioral and electromagnetic studies. In recent years, neurocognitive word production research has seen a major change toward a hypothesis-testing approach. This approach is characterized by the design of experimental variables modulating single component processes of word production and testing for predicted effects on spatial or temporal neurocognitive signatures of these components. This change was accompanied by the development of a broader spectrum of measurement and analysis techniques. The article reviews the findings of recent studies using the new approach. The time course assumptions of Indefrey and Levelt (2004) have largely been confirmed requiring only minor adaptations. Adaptations of the brain structure/function relationships proposed by Indefrey and Levelt (2004) include the precise role of subregions of the left inferior frontal gyrus as well as a probable, yet to date unclear role of the inferior parietal cortex in word production.
Schizophrenia has been conceptualized as a failure of cognitive integration, and abnormalities in neural circuitry (particularly inhibitory interneurons) have been proposed as a basis for this disorder. We used measures of phase locking and phase coherence in the scalp-recorded electroencephalogram to examine the synchronization of neural circuits in schizophrenia. Compared with matched control subjects, schizophrenia patients demonstrated: (1) absence of the posterior component of the early visual gamma band response to Gestalt stimuli; (2) abnormalities in the topography, latency, and frequency of the anterior component of this response; (3) delayed onset of phase coherence changes; and (4) the pattern of anterior-posterior coherence increases in response to Gestalt stimuli found in controls was replaced by a pattern of interhemispheric coherence decreases in patients. These findings support the hypothesis that schizophrenia is associated with impaired neural circuitry demonstrated as a failure of gamma band synchronization, especially in the 40 Hz range.
Objective
We sought to examine the relation between cannabis abuse and the symptomatic course of recent-onset schizophrenia and related disorders.
Design
A prospective cohort study over a year using monthly Brief Psychiatric Rating Scale assessments.
Participants
Cannabis-abusing patients (n=24) were compared with nonabusers (n=69). Eleven patients were mild and 13 were heavy cannabis-abusing patients.
Results
Significantly more and earlier psychotic relapses occurred in the cannabis-abusing group (P=.03). This association became stronger when mild and heavy cannabis abuse were distinguished (P=.002). No confounding effect of other variables, eg, other street drugs, was found. In all but one patient, cannabis abuse preceded the onset of the first psychotic symptoms for at least 1 year.
Conclusions
Cannabis abuse and particularly heavy abuse can be considered a stressor eliciting relapse in patients with schizophrenia and related disorders and possibly a premorbid precipitant.
SUMMARYA modification of an earlier rating scale for extrapyramidal system disturbance is described, and evidence for the validity and reliability of the scale is presented. The usefulness of the scale in studies of neuroleptic drugs is discussed. By its application it is possible to quantify extrapyramidal side effects and to separate them into four principal factors.
Behavioral, biochemical and recent electrophysiological data have increasingly implicated the involvement of dopamine in the central actions of cannabinoid compounds. However, the site and mechanism by which cannabinoids stimulate dopamine systems has been somewhat controversial. Central opioid systems have also been suggested to play a role in some cannabinoid-induced behaviors as evidenced by their attenuation in the presence of the opioid antagonist naloxone. However, recent studies using the cannabinoid receptor-selective antagonist SR141716A suggest that the central actions of psychoactive cannabinoids are mediated principally through activation of CB1 receptors. Using single cell electrophysiological recordings in the rat we assessed the effects of both SR141716A and naloxone on delta9-tetrahydrocannabinol (THC)-induced activation of ventral tegmental dopamine neurons. While dopamine cell firing was dose-dependently increased following cumulative dosing with delta9-THC it was partially or completely inhibited following pretreatment with 0.5 and 2 mg/kg SR141716A, respectively. However, 1 and 10 mg/kg naloxone failed to alter the response to delta9-THC. These data provide the first evidence that delta9-THC-induced changes in mesolimbic dopamine neuronal activity are mediated by the CB1 cannabinoid receptor, but a causal link for the involvement of opioid systems could not be established.
The effects of morphine and Δ9-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
Δ9-Tetrahydrocannabinol (Δ9-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of Δ9-THC were similar for the groups after IV injection of 5.0 mg Δ9-THC, but the AUC0–240 min showed a trend towards lower values for the heavy user group. To achieve a maximum desired “high”, both groups smoked similar amounts (about 13 mg) of Δ9-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked Δ9-THC was significantly higher for the heavy users (heavy users 23±16% vs 10±7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers.
Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and “high”, was quite comparable to that of light users.
The present study does not suggest that tolerance readily develops in heavy users.
The pharmacological interaction between cannabidiol (CBD) and (−)δ
9-trans-tetrahydrocannabinol (δ
9-THC) has been studied in rabbits, mice and rats by administering mixtures containing varying amounts of both substances. CBD blocked the following effects of δ
9-THC: catatonia in mice, corneal areflexia in rabbits, the increased defecation and decreased ambulation after chronic treatment and exposures of rats in an open field arena, and the aggressiveness of rats previously stressed by REM sleep deprivation. On the other hand, CBD potentiated the δ
9-THC-induced analgesia in mice and the δ
9-THC-impairing effect on climbing rope performance of rats.
These interactions are tentatively explained by postulating that CBD directly antagonizes the excitatory effects and/or indirectly potentiates the depressant effects of δ
9-THC.
Objective:
The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects.
Method:
Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM.
Results:
No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms.
Conclusions:
In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.
New data strengthen the idea of a prominent role for endocannabinoids in the modulation of a wide variety of neurobiological functions. Among these, one of the most important is the control of movement. This finding is supported by 3 lines of evidence: (1) the demonstration of a powerful action, mostly inhibitory in nature, of synthetic and plant-derived cannabinoids and, more recently, of endocannabinoids on motor activity; (2) the presence of the cannabinoid CB1 receptor subtype and the recent description of endocannabinoids in the basal ganglia and the cerebellum, the areas that control movement; and (3) the fact that CB1 receptor binding was altered in the basal ganglia of humans affected by several neurological diseases and also of rodents with experimentally induced motor disorders. Based on this evidence, it has been suggested that new synthetic compounds that act at key steps of endocannabinoid activity (i.e., more-stable analogs of endocannabinoids, inhibitors of endocannabinoid reuptake or metabolism, antagonists of CB1 receptors) might be of interest for their potential use as therapeutic agents in a variety of pathologies affecting extrapyramidal structures, such as Parkinson's and Huntington's diseases. Currently, only a few data exist in the literature studying such relationships in humans, but an increasing number of journal articles are revealing the importance of this new neuromodulatory system and arguing in favour of the funding of more extensive research in this field. The present article will review the current knowledge of this neuromodulatory system, trying to establish the future lines for research on the therapeutic potential of the endocannabinoid system in motor disorders.
In addition to their ability to change the electrical properties of neurons, evidence suggests that neurotransmitters are able to alter the cell's metabolism. Transmitter phenotype is labile and expression might be regulated, during development, by the cellular environment of neurons. The study of a key enzyme in the synthesis of catecholamines, tyrosine hydroxylase (TH), has provided clues about these adaptive responses. This enzyme has a large molecular diversity, resulting from the differential splicing of its mRNA, which is tissue-specific and might result in long-term changes in activity of the enzyme and, therefore, in the availability of neurotransmitter at various synapses. The presence of different DNA sequences at the TH locus confers susceptibility to various disorders of the brain, including manic-depressive illness and schizophrenia. Indeed, an association between a rare variant allele of the gene encoding TH and the occurrence of schizophrenia has been found in several populations. New techniques being developed to treat diseases such as Parkinson's disease involve various gene therapies, including a method of transferring genes directly into nerve cells using an adenovirus-based system. Trends Neurosci. (1996) 19, 191–196
Immunohistochemical distribution of cannabinoid receptors in the adult rat brain was studied using specific purified antibodies against the amino-terminus of the CB1 receptor. Our results generally agree well with the previous studies using CB1 receptor autoradiography and messenger RNA in situ hybridization. However, because of its greater resolution, immunohistochemistry allowed identification of particular neuronal cells and fibers that possess cannabinoid receptors. CB1-like immunoreactivity was found in axons, cell bodies and dendrites, where it appeared as puncta in somata and processes. Both intensely and moderately or lightly stained neurons were observed. The intensely stained neurons were dispersed and only occur in cortical structures including hippocampal formation and olfactory bulb. Moderately or lightly stained neurons were found in caudate-putamen and amygdala. In the hippocampal formation only intensely stained neurons were observed. The cell bodies of pyramidal neurons in CA1 and CA3 fields appeared to be unstained but surrounded by a dense plexus of immunoreactive fibers. The granule cells in the dentate area were also immunonegative. Many intensely stained neurons were located at the base of the granule cell layer. CB1-like immunoreactive neurons and fibers were also found in the somatosensory, cingulate, perirhinal, entorhinal and piriform cortices, in claustrum, amygdaloid nuclei, nucleus accumbens and septum. Beaded immunoreactive fibers were detected in periaqueductal gray, nucleus tractus solitarius, spinal trigeminal tract and nucleus, dorsal horn and lamina X of the spinal cord. A triangular cap-like mass of immunoreactivity was found to surround the basal part of the Purkinje cell body in the cerebellum. Only small, lightly stained cells were found in the molecular layer in the cerebellum close to the Purkinje cell layer. The CB1 receptor is widely distributed in the forebrain and has a more restricted distribution in the hindbrain and the spinal cord. It appears to be expressed on cell bodies, dendrites and axons. According to the location and morphology, many, but not all, CB1-like immunoreactive neurons appear to be GABAergic. Therefore, cannabinoids and cannabinoid receptors may play a role in modulating GABAergic neurons.
Behavioral, biochemical and recent electrophysiological data have increasingly implicated the involvement of dopamine in the central actions of cannabinoid compounds. However, the site and mechanism by which cannabinoids stimulate dopamine systems has been somewhat controversial. Central opioid systems have also been suggested to play a role in some cannabinoid-induced behaviors as evidenced by their attenuation in the presence of the opioid antagonist naloxone. However, recent studies using the cannabinoid receptor-selective antagonist SR141716A suggest that the central actions of psychoactive cannabinoids are mediated principally through activation of CB1 receptors. Using single cell electrophysiological recordings in the rat we assessed the effects of both SR141716A and naloxone on Δ9-tetrahydrocannabinol (THC)-induced activation of ventral tegmental dopamine neurons. While dopamine cell firing was dose-dependently increased following cumulative dosing with Δ9-THC it was partially or completely inhibited following pretreatment with 0.5 and 2 mg/kg SR14171 6A, respectively. However, 1 and 10 mg/kg naloxone failed to alter the response to Δ9-THC. These data provide the first evidence that Δ9-THC-induced changes in mesolimbic dopamine neuronal activity are mediated by the CB1 cannabinoid receptor, but a causal link for the involvement of opioid systems could not be established.
Preface to Second Edition. Mixed Model Notations. 1 Introduction. 1.1 The Use of Mixed Models. 1.2 Introductory Example. 1.3 A Multi-Centre Hypertension Trial. 1.4 Repeated Measures Data. 1.5 More aboutMixed Models. 1.6 Some Useful Definitions. 2 NormalMixed Models. 2.1 Model Definition. 2.2 Model Fitting Methods. 2.3 The Bayesian Approach. 2.4 Practical Application and Interpretation. 2.5 Example. 3 Generalised Linear MixedModels. 3.1 Generalised Linear Models. 3.2 Generalised Linear Mixed Models. 3.3 Practical Application and Interpretation. 3.4 Example. 4 Mixed Models for Categorical Data. 4.1 Ordinal Logistic Regression (Fixed Effects Model). 4.2 Mixed Ordinal Logistic Regression. 4.3 Mixed Models for Unordered Categorical Data. 4.4 Practical Application and Interpretation. 4.5 Example. 5 Multi-Centre Trials and Meta-Analyses. 5.1 Introduction to Multi-Centre Trials. 5.2 The Implications of using Different Analysis Models. 5.3 Example: A Multi-Centre Trial. 5.4 Practical Application and Interpretation. 5.5 Sample Size Estimation. 5.6 Meta-Analysis. 5.7 Example: Meta-analysis. 6 RepeatedMeasures Data. 6.1 Introduction. 6.2 Covariance Pattern Models. 6.3 Example: Covariance Pattern Models for Normal Data. 6.4 Example: Covariance Pattern Models for Count Data. 6.5 Random Coefficients Models. 6.6 Examples of Random Coefficients Models. 6.7 Sample Size Estimation. 7 Cross-Over Trials. 7.1 Introduction. 7.2 Advantages of Mixed Models in Cross-Over Trials. 7.3 The AB/BA Cross-Over Trial. 7.4 Higher Order Complete Block Designs. 7.5 Incomplete Block Designs. 7.6 Optimal Designs. 7.7 Covariance Pattern Models. 7.8 Analysis of Binary Data. 7.9 Analysis of Categorical Data. 7.10 Use of Results from Random Effects Models in Trial Design. 7.11 General Points. 8 Other Applications of MixedModels. 8.1 Trials with Repeated Measurements within Visits. 8.2 Multi-Centre Trials with Repeated Measurements. 8.3 Multi-Centre Cross-Over Trials. 8.4 Hierarchical Multi-Centre Trials and Meta-Analysis. 8.5 Matched Case-Control Studies. 8.6 Different Variances for Treatment Groups in a Simple Between-Patient Trial. 8.7 Estimating Variance Components in an Animal Physiology Trial. 8.8 Inter- and Intra-Observer Variation in Foetal Scan Measurements. 8.9 Components of Variation and Mean Estimates in a Cardiology Experiment. 8.10 Cluster Sample Surveys. 8.11 Small AreaMortality Estimates. 8.12 Estimating Surgeon Performance. 8.13 Event History Analysis. 8.14 A Laboratory Study Using aWithin-Subject 4 x 4 Factorial Design. 8.15 Bioequivalence Studies with Replicate Cross-Over Designs. 8.16 Cluster Randomised Trials. 9 Software for Fitting MixedModels. 9.1 Packages for Fitting Mixed Models. 9.2 Basic use of PROC MIXED. 9.3 Using SAS to Fit Mixed Models to Non-Normal Data. Glossary. References. Index.
Wild growing Cannabis from different altitudes and locations was collected in northern India. Plant material from each collection was analyzed quantitatively for ten cannabinoids by GC. The average total cannabinoid content of plants growing above 2,000 m was 1.33 %, whereas below 2,000 m the average total cannabinoid content was 2.74 %. Morphological characteristics were recorded. Data obtained from wild growing Indian Cannabis (twenty variants) are compared with data obtained from the same variants grown in Mississippi, USA.
Previous work posits that severity of substance abuse and severity of schizophrenic symptoms should be linked by either or both of two mechanisms: self-regulation of symptoms and drug-induced exacerbation of symptoms. Research on these relationships has yielded mixed results. We examined the interrelationships of schizophrenic symptoms and substance abuse in 172 patients with co-occurring disorders. Relationships were weak or nonexistent, without any consistent pattern. Our findings do not support the view that substances are used to self-regulate symptoms. In addition, our results suggest that substance abuse may lead to higher rates of institutionalization through mechanisms other than by exacerbating symptoms.
It was shown recently that Δ9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10−6 and 10−5 m). The CB1 cannabinoid receptor antagonist SR141716A (10−6 m) prevented the inhibition produced by WIN55212-2 (10−5 m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10−5 m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10−5 m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.
A group of sixty-six adult subjects was given the task of producing as many words as possible beginning with specified letters of the alphabet. The number of words produced during a period of 60 sec correlated highly both with a frequency count derived from the Thorndike-Lorge norms and with estimates derived from the dictionary of the number of words in the English language beginning with each letter. In a second experiment, eight letters representing three levels of difficulty as found in normal subjects were given to thirty brain-damaged and thirty hospitalized control patients. Results in terms of verbal productivity indicated that, for patients of high intelligence, difficult letters (i.e. J and U) showed the greatest discrimination. On the other hand, for patients of low intelligence, easy letters (i.e. F, S, P and T) were more effective in differentiating the brain-damage and control groups. The findings also indicated that difficult letters may be particularly effective in distinguishing between patients with right and left hemisphere damage. An analysis of order of presentation indicated that practice and fatigue effects were not related to verbal fluency when as many as eight letters were administered. It is suggested that the addition of difficult letters to standard word fluency tests may yield more precise discriminations between brain-damaged and control patients when overall level of intellectual functioning is taken into account.
Three experienced marijuana smokers participated in four 2-day experimental sessions in which they smoked either 0, 1, or 2 marijuana cigarettes containing 2.57% Δ9-tetrahydrocannabinol (THC) at two different times on the first day. A battery of physiological, subjective, and performance measures was repeated throughout day 1 to assess acute effects and on day 2 to measure any residual effects of marijuana. Blood samples were also repeatedly collected to examine the relationship between plasma levels and pharmacological effects of THC. Acutely, marijuana increased heart rate and subjective ratings of drug effects and slightly impaired performance on a circular lights task in all subjects. Performance was also impaired (decreased accuracy and increased response time) on serial addition/subtraction and digit recall tasks on day 1 in two subjects. On day 2, tachycardia and subjective effects of marijuana were not observed. Performance remained impaired on the arithmetic and recall tasks on day 2, although the decrements were not as large as those observed on day 1. In general, plasma THC levels covaried with the other measures. These preliminary results suggest that marijuana can adversely affect complex human performance up to 24 hours after smoking.
The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo–controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine. We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls. Schizophrenics experienced a brief ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals. These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia. Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls.
Implicit learning was examined in 15 Huntington's disease (HD) patients and 15 control subjects (NC) using a semantic decision-making task. HD patients demonstrated only slightly reduced priming; like NC subjects, their decision times decreased over repeated presentations, though to a somewhat lesser degree. On explicit recognition testing, the HD group made significantly more false positive errors than did the control group, suggesting an impairment of effortful retrieval. The groups displayed equivalent retention of implicitly learned material after 6 months. The striatal neuronal loss of early Huntington's disease does not markedly affect priming or retention of primed stimuli, but may alter explicit memory judgements.
Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol (Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects.
Marijuana has a long history of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and until recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders.
The CB1-type cannabinoid receptor mediates physiologic effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient of the drug marijuana. In this report, the authors analyse the expression of CB1 in the rat brain by using antibodies to the C-terminal 13 amino acids of the receptor. Western blot analysis of rat brain membranes revealed a prominent immunoreactive band with a molecular mass (≈53 kDa) consistent with that predicted for CB1 from the rat cDNA sequence. In addition, however, less intense immunoreactive bands corresponding to glycosylated (≈62 kDa) and putative N-terminally shorter (≈45 kDa) isoforms of CB1 were detected. The distribution of CB1-immunoreactivity in rat brain was similar to the distribution of binding sites for radiolabelled cannabinoids, with high levels of expression in the olfactory system, the hippocampal formation, the basal ganglia, the cerebellum, and the neocortex. This provides important evidence that CB1 is likely to be largely responsible for mediating effects of cannabinoids in the brain. CB1 immunoreactivity was associated with nerve fibre systems and axon terminals but was not detected in neuronal somata. This is consistent with the presynaptic inhibitory effects of cannabinoids on neurotransmitter release in the brain. Detailed immunocytochemical analysis of anatomically or functionally related regions of the brain revealed the location of CB1 receptors within identified neural circuits. Determination of the cellular and subcellular location of CB1 within known neuronal circuits of the brain provides an anatomic framework for interpretation of the neurophysiologic and behavioural effects of cannabinoids. J. Comp. Neurol. 422:159–171, 2000.
We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.
Injection of delta 1-tetrahydrocannabinol (THC) into mice increased the uptake into brain synaptosomes of radioactive DA, NE, 5-HT and GABA, with the effect on GABA being the greatest; uptake of leucine was not stimulated, indicating that THC does not facilitate the transport of amino acids in general. The effect of THC was stereospecific because pretreatment with the non-psychoactive isomer, (+) delta 6-THC had no effect on uptake of DA into cortical synaptosomes. The effect on DA uptake was correlated with psychoactive potency. THC enhanced uptake more than did SP-111 (a water soluble ester of THC but less potent than THC) and much more than cannabidiol (a non-psychoactive ingredient of marijuana). THC increased the uptake of DA into striatal synaptosomes but much less than into cortical synaptosomes. The enhancing effect of THC on uptake in cortex showed tolerance after chronic (1 week) treatment with THC. Catecholaminergic receptor antagonists (chlorpromazine, propranolol), like THC, stimulated the uptake of DA or NE into cortical synaptosomer. In contrast, pretreatment with MAO (pargyline) or uptake (tricyclic antidepressants) inhibitors, or with amphetamine, decreased uptake. Thus THC does not inhibit MAO uptake, or stimulate the release of catecholamines but may interact with a receptor. The notion of a THC--receptor interaction is supported by behavioral experiments.
Sixteen college-educated male subjects were tested on free-recall lists during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9-tetrahydrocannabinol and during placebo conditions. On each testing day subjects studied six lists using a regular overt rehearsal procedure and six lists using an association-overt rehearsal procedure in which they were to rehearse alound both list items and associations to those items. Both marijuana and the association-rehearsal procedure reduced the number of correct recalls and increased the number of intrusions (nonlist items which were incorrectly recalled as having been on the list to be learned). The intrusions were divided into three categories: a) words found on prior lists; b) associates spoken during the rehearsal; or c) totally new works not previously mentioned. Marijuana significantly increased the number of new intrusions; the association-rehearsal procedure did not. This result suggests that one of the effects of marijuana on cognitive functions in humans is to increase the number of intrusive thoughts and this may be the mechanism involved in some of the thought disorder observed with marijuana intoxication.
The effect of marijuana on memory as measured by free recall and recognition, pulse rate and self ratings of intoxication was evaluated in 16 male volunteers. Marijuana containing 0, 5, 10 or 15 mg delta9-THC was administered to all subjects by smoking in 4 sessions separated by a 1 week interval. Free recall was reduced in a dose related manner by the drug, but recognition memory was unaffected. A 2 sec word presentation rate produced inferior recall in comparison to a 4 sec rate, but this variable did not interact with drug condition. Intrusion errors increased following intoxication but this effect was not systematically related to dosage of delta9-THC. Both pulse rate and self ratings of intoxication increased with dosage.
delta 9-Tetrahydrocannabinol (delta 9-THC) has been reported to attenuate both reserpine-induced serotonin depletion and reserpine-induced hypothermia. We have observed that delta 9-THC preincubation led to a dose-responsive increase in the amount of 3H-reserpine bound to a crude mitochondrial fraction of rat forebrain. The experiments reported here further characterize this phenomenon. Preincubation with delta 9-THC produced a shift in the localization of 3H-reserpine from the incubation medium and the microsomal supernatant (decrease of 66%) to the crude mitochondrial (CM) pellet (increase of 154%). The CM pellet was subfractionated both by differential centrifugation after osmotic shock and by layering on a five-step discontinuous sucrose gradient and centrifuging at 80,000 x g. Osmotic shock with 0.032 M sucrose and centrifugation revealed that the delta 9-THC-induced increase in 3H-reserpine was contained in both the synaptic vesicle fraction (247%) and the fraction containing myelin, ruptured synaptosomes and mitochondria (324%). Separating the CM fraction into five component parts showed that delta 9-THC increased the 3H-reserpine bound by about 275% in the three fractions containing myelin, membrane fragments or mitochondria. Even more dramatic increases (greater than 1000%) were observed in the two fractions containing cholinergic and non-cholinergic nerve endings. In addition, we have determined that many other drugs which are believed to have membrane mediated mechanisms have no effect on the amount of 3H-reserpine bound to the crude mitochondrial fraction. Although other possibilities exist, these data support the hypothesis that delta 9-THC retards the action of reserpine by altering the normal distribution of reserpine in various membrane components of the rat brain.
The effects of δ
9-tetrahydrocannabinol (δ
9-THC) and alcohol, and their combination, on divided attention performance were compared for cannabis users and non-users of both sexes. Performance by all subjects was significantly impaired following 2.6 and 5.2 mg δ
9-THC but not at blood alcohol concentrations of 48 and 96 mg/100 ml. The combined effect of the 2 drugs depended upon prior experience with cannabis. A synergistic action occurred in non-users while an antagonistic effect occurred in the group of users. Differences in the alcohol effects between users and non-users provided evidence of cross-tolerance between cannabis and alcohol.
The interaction of delta9-tetrahydrocannabinol (delta9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg delta9-THC, 12.5 mg delta9-THC + 25 mg CBN, and 25 mg delta9-THC + 50 mg CBN (orally). Administrations were spaced 1 week apart. With physiological measures, delta9-THC produced an increase in heart rate while CBN did not. When combined, no change of the delta9-THC effect occurred. No changes occurred on the electrocardiogram, blood pressure, or body temperature. With psychophysical measures no changes occurred in pain thresholds or skin sensitivity as a function of drug treatment. In time estimates of the passage of 1 minute, delta9-THC alone produced underestimates of the passage of 1 minute and CBN alone had no effect. In combination the two drugs had a tendency to produce significant overestimates and underestimates of the passage of 1 minute. On a 66-item adjective-pair drug reaction scale, the volunteers reported feeling drugged, drunk, dizzy, and drowsy under the delta9-THC condition, but not under the CBN condition. With combined drug treatment, volunteers reported feeling more drugged, drunk, dizzy, and drowsy than under the delta9-THC condition alone. None of the drug treatments produced significant changes on other items which included items on perception, emotion, cognition and sociability. It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used.