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1.  Polysubstance Use in Cannabis Users Referred for Treatment: Drug Use Profiles, Psychiatric Comorbidity and Cannabis-Related Beliefs 
Background: Population-based surveys demonstrate cannabis users are more likely to use both illicit and licit substances, compared with non-cannabis users. Few studies have examined the substance use profiles of cannabis users referred for treatment. Co-existing mental health symptoms and underlying cannabis-related beliefs associated with these profiles remains unexplored.
Methods: Comprehensive drug use and dependence severity (Severity of Dependence Scale-Cannabis) data were collected on a sample of 826 cannabis users referred for treatment. Patients completed the General Health Questionnaire, Cannabis Expectancy Questionnaire, Cannabis Refusal Self-Efficacy Questionnaire, and Positive Symptoms and Manic-Excitement subscales of the Brief Psychiatric Rating Scale. Latent class analysis was performed on last month use of drugs to identify patterns of multiple drug use. Mental health comorbidity and cannabis beliefs were examined by identified drug use pattern.
Results: A three-class solution provided the best fit to the data: (1) cannabis and tobacco users (n = 176), (2) cannabis, tobacco, and alcohol users (n = 498), and (3) wide-ranging substance users (n = 132). Wide-ranging substance users (3) reported higher levels of cannabis dependence severity, negative cannabis expectancies, lower opportunistic, and emotional relief self-efficacy, higher levels of depression and anxiety and higher manic-excitement and positive psychotic symptoms.
Conclusion: In a sample of cannabis users referred for treatment, wide-ranging substance use was associated with elevated risk on measures of cannabis dependence, co-morbid psychopathology, and dysfunctional cannabis cognitions. These findings have implications for cognitive-behavioral assessment and treatment.
doi:10.3389/fpsyt.2013.00079
PMCID: PMC3736050  PMID: 23966956
cannabis; latent class; drugs; comorbidity; expectancy; self-efficacy; treatment seeking
2.  DRD2 and DRD4 in relation to regular alcohol and cannabis use among adolescents: Does parenting modify the impact of genetic vulnerability? The TRAILS study 
Drug and alcohol dependence  2010;115(0):35-42.
Aims
The aims of the present study were to determine the direct effect of DRD2 and DRD4, as well as their interaction with parenting (i.e. rejection, overprotection and emotional warmth), on the development of regular alcohol and cannabis use in 1192 Dutch adolescents from the general population.
Methods
Information was obtained by self-report questionnaires. Perceived rejection, overprotection and emotional warmth were assessed at age 10–12. Regular alcohol and cannabis use were determined at age 15–18 and defined as the consumption of alcohol on 10 or more occasions in the past four weeks, and the use of cannabis on 4 or more occasions in the past four weeks. Models were adjusted for age, sex, parental alcohol or cannabis use, and externalizing behavior.
Results
Carrying the A1 allele of the DRD2 TaqIA polymorphism, or the 7 repeat DRD4, was not directly related to regular alcohol or cannabis use. In addition, adolescent carriers of these genetic risk markers were not more susceptible to the influence of less optimal parenting. Main effects for parenting indicated that overprotection increased the risk of regular alcohol use, whereas the risk of cannabis use was enhanced by parental rejection and buffered by emotional warmth.
Conclusions
Our findings do not support an association between DRD2/DRD4 and regular alcohol and cannabis use in adolescents. Given the substance-specific influences of rejection, overprotection and emotional warmth, these parenting factors might be promising candidates for prevention work.
doi:10.1016/j.drugalcdep.2010.10.008
PMCID: PMC4068118  PMID: 21106310
Cannabis; Alcohol; Parenting; Adolescence; DRD2; DRD4; Gene–environment interaction
3.  Reaching out towards cannabis: approach-bias in heavy cannabis users predicts changes in cannabis use 
Addiction (Abingdon, England)  2011;106(9):1667-1674.
Aims
Repeated drug exposure can lead to an approach-bias, i.e. the relatively automatically triggered tendencies to approach rather that avoid drug-related stimuli. Our main aim was to study this approach-bias in heavy cannabis users with the newly developed cannabis Approach Avoidance Task (cannabis-AAT) and to investigate the predictive relationship between an approach-bias for cannabis-related materials and levels of cannabis use, craving, and the course of cannabis use.
Design, settings and participants
Cross-sectional assessment and six-month follow-up in 32 heavy cannabis users and 39 non-using controls.
Measurements
Approach and avoidance action-tendencies towards cannabis and neutral images were assessed with the cannabis AAT. During the AAT, participants pulled or pushed a joystick in response to image orientation. To generate additional sense of approach or avoidance, pulling the joystick increased picture size while pushing decreased it. Craving was measured pre- and post-test with the multi-factorial Marijuana Craving Questionnaire (MCQ). Cannabis use frequencies and levels of dependence were measured at baseline and after a six-month follow-up.
Findings
Heavy cannabis users demonstrated an approach-bias for cannabis images, as compared to controls. The approach-bias predicted changes in cannabis use at six-month follow-up. The pre-test MCQ emotionality and expectancy factor were associated negatively with the approach-bias. No effects were found on levels of cannabis dependence.
Conclusions
Heavy cannabis users with a strong approach-bias for cannabis are more likely to increase their cannabis use. This approach-bias could be used as a predictor of the course of cannabis use to identify individuals at risk from increasing cannabis use.
doi:10.1111/j.1360-0443.2011.03475.x
PMCID: PMC3178782  PMID: 21518067
Approach avoidance task; approach-bias; cannabis; cannabis use disorder; craving; dependence
4.  Simultaneous cannabis and tobacco use and cannabis-related outcomes in young women 
Drug and alcohol dependence  2008;101(1-2):8-12.
Compared to those who reported a lifetime co-occurrence of cannabis and tobacco use, individuals who report simultaneous use of cannabis and tobacco are more likely to also report higher rates of substance-related problems and psychopathology. In a sample of young women, we examine (a) co-occurring use, or whether regular cigarette smoking is associated with increased cannabis involvement and (b) simultaneous use, a special form of co-occurring use where cannabis and cigarettes are typically used on the same occasion to test whether those who use cannabis and tobacco simultaneously are also more likely to report greater cannabis involvement and (c) the extent to which latent genetic and environmental factors contribute to simultaneous use in those with a history of co-occurring cannabis use and regular cigarette smoking. Women (N=3,427) who report regular cigarette smoking are 4.5–9.5 times more likely to report co-occurring cannabis use and other stages of cannabis involvement, including DSM-IV cannabis abuse and dependence. In those women who report co-occurring regular cigarette smoking and lifetime cannabis use (N=1,073), simultaneous use of cannabis and tobacco was associated with increased likelihood of negative cannabis-related outcomes. Simultaneous users were 1.6 times more likely to meet criteria for DSM-IV cannabis abuse, even after controlling for early covariates and for prior stages of cannabis involvement. Simultaneous use was not heritable, and twin similarity was attributable to shared environmental factors (31%). While our study does not determine causality between simultaneous tobacco-cannabis use and cannabis involvement, results indicate that simultaneous use is potentially a marker for more severe psychosocial consequences associated with cannabis use.
doi:10.1016/j.drugalcdep.2008.10.019
PMCID: PMC3021959  PMID: 19081202
Simultaneous use; cannabis; tobacco; abuse; dependence; twin
5.  The Interplay between Parental Monitoring and the Dopamine D4 Receptor Gene in Adolescent Cannabis Use 
PLoS ONE  2012;7(11):e49432.
Background
Both environmental risk and genetic variation is believed to play a role in substance use. A candidate environmental variable is parenting. Recent studies have found support for the idea that the dopamine system affects the susceptibility to environmental influences. In the present study we will examine the interplay between effects of parental monitoring and the presence of the DRD4 7-repeat allele in adolescent lifetime cannabis use and the developmental course of cannabis use.
Methods
A total of 311 adolescents participated in a five-wave longitudinal design. First, we conducted logistic regression analyses to examine the prospective associations between parental monitoring, the DRD4 polymorphism, their interaction and lifetime cannabis use. Second, individual growth parameters were calculated for frequency of cannabis use. Linear regression was used to assess the relationship between parental monitoring, the DRD4 polymorphism, their interaction, and the frequency of cannabis use.
Results
There were no significant main effects of parental monitoring or the DRD4 polymorphism. However, both analyses showed that over a period of four years, a) when experiencing low levels of parental monitoring, individuals with the 7-repeat allele were more likely to show lifetime cannabis use and a stronger increase in frequency of cannabis use than individuals without this allele; b) when experiencing high levels of parental monitoring, individuals with the 7-repeat allele were less likely to show lifetime cannabis use and they showed a smaller increase in frequency of cannabis use than individuals without the 7-repeat allele.
Conclusions
This study shows that carriers of the DRD4 7-repeat allele are disproportionally affected by the negative and positive effects of parental monitoring such that carriers of the DRD4 7-repeat allele, as compared to non-carriers, are more likely to use cannabis when levels of parental monitoring are low, and less likely to use cannabis when parental monitoring levels are high.
doi:10.1371/journal.pone.0049432
PMCID: PMC3509099  PMID: 23209577
6.  PROENKEPHALIN MEDIATES THE ENDURING EFFECTS OF ADOLESCENT CANNABIS EXPOSURE ASSOCIATED WITH ADULT OPIATE VULNERABILITY 
Biological psychiatry  2012;72(10):803-810.
Background
Marijuana use by teenagers often predates the use of harder drugs, but the neurobiological underpinnings of such vulnerability are unknown. Animal studies suggest enhanced heroin self-administration (SA) and dysregulation of the endogenous opioid system in the nucleus accumbens shell (NAcsh) of adults following adolescent Δ9-tetrahydrocannabinol (THC) exposure. However, a causal link between Penk expression and vulnerability to heroin has yet to be established.
Methods
To investigate the functional significance of NAcsh Penk tone, selective viral-mediated knockdown and overexpression of Penk was performed, followed by analysis of subsequent heroin SA behavior. To determine whether adolescent THC exposure was associated with chromatin alteration, we analyzed levels of histone H3 methylation in the NAcsh via ChIP at five sites flanking the Penk gene transcription start site.
Results
Here, we show that regulation of the proenkephalin (Penk) opioid neuropeptide gene in NAcsh directly regulates heroin SA behavior. Selective viral-mediated knockdown of Penk in striatopallidal neurons attenuates heroin SA in adolescent THC-exposed rats, whereas Penk overexpression potentiates heroin SA in THC-naïve rats. Furthermore, we report that adolescent THC exposure mediates Penk upregulation through reduction of histone H3 lysine 9 (H3K9) methylation in the NAcsh, thereby disrupting the normal developmental pattern of H3K9 methylation.
Conclusions
These data establish a direct association between THC-induced NAcsh Penk upregulation and heroin SA and indicate that epigenetic dysregulation of Penk underlies the long-term effects of THC.
doi:10.1016/j.biopsych.2012.04.026
PMCID: PMC3440551  PMID: 22683090
drug addiction; marijuana; rat; nucleus accumbens; striatopallidal; epigenetics
7.  Associations between Cannabinoid Receptor-1 (CNR1) Variation and Hippocampus and Amygdala Volumes in Heavy Cannabis Users 
Neuropsychopharmacology  2012;37(11):2368-2376.
Heavy cannabis users display smaller amygdalae and hippocampi than controls, and genetic variation accounts for a large proportion of variance in liability to cannabis dependence (CD). A single nucleotide polymorphism in the cannabis receptor-1 gene (CNR1), rs2023239, has been associated with CD diagnosis and intermediate phenotypes, including abstinence-induced withdrawal, cue-elicited craving, and parahippocampal activation to cannabis cues. This study compared hippocampal and amygdalar volumes (potential CD intermediate phenotypes) between heavy cannabis users and healthy controls, and analyzed interactions between group, rs2023239 variation, and the volumes of these structures. Ninety-four heavy cannabis users participated, of whom 37 (14 men, 23 women; mean age=27.8) were matched to 37 healthy controls (14 men, 23 women; mean age=27.3) for case-control analyses. Controlling for total intracranial volume and other confounding variables, matched cannabis users had smaller bilateral hippocampi (left, p=0.002; right, p=0.001) and left amygdalae (p=0.01) than controls. When genotype was considered in the case-control analyses, there was a group by genotype interaction, such that the rs2023239 G allele predicted lower volume of bilateral hippocampi among cannabis users relative to controls (both p<0.001). This interaction persisted when all 94 cannabis users were compared to controls. There were no group by genotype interactions on amygdalar volume. These data replicate previous findings of reduced hippocampal and amygdalar volume among heavy cannabis users, and suggest that CNR1 rs2023239 variation may predispose smaller hippocampal volume after heavy cannabis use. This association should be tested in future studies of brain volume differences in CD.
doi:10.1038/npp.2012.92
PMCID: PMC3442352  PMID: 22669173
marijuana; genetics; endocannabinoid; hippocampus; amygdala; addiction & substance abuse; amygdala; endocannabinoid; genetics; hippocampus; imaging; clinical or preclinical; marijuana; neuroanatomy; neurogenetics
8.  Adolescent Cannabis Use Increases Risk for Cocaine-Induced Paranoia 
Drug and alcohol dependence  2009;107(2-3):196.
Cannabis can produce and/or exacerbate psychotic symptoms in vulnerable individuals. Early exposure to cannabis, particularly in combination with genetic factors, increases the risk of a subsequent, primary, psychotic disorder. Because paranoia is a common feature of stimulant abuse and cocaine dependent individuals frequently endorse a history of cannabis abuse, we examined whether early cannabis exposure, in conjunction with polymorphic variation in the catechol-O-methyl transferase gene (COMT Val158Met), influences the risk for cocaine-induced paranoia (CIP).
Methods
Cannabis-use history was obtained in 1140 cocaine-dependent individuals from a family-based (affected sibling pair) study using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Logistic regression and generalized estimating equations analyses were used to examine the role of adolescent-onset cannabis use (≤ 15 yrs of age) on CIP risk, both controlling for previously implicated CIP risk factors and familial relationships, and considering potential interactions with COMT Val158Met genotype.
Results
Cocaine-dependent individuals who endorsed CIP had significantly higher rates of adolescent-onset cannabis use than those without CIP (62.2% vs. 50.2%; χ2 = 15.2, df = 1, p < 0.0001), a finding that remained after controlling for sibling correlations and other risk factors. There were no effects of COMT genotype or genotype by early cannabis onset interactions. A modest (OR = 1.4) and nearly significant (p = 0.053) effect of CIP status in probands on CIP status in siblings was also noted.
Conclusions
Adolescent-onset cannabis use increases the risk of CIP in cocaine dependent individuals. COMT genotype and its interaction with early cannabis exposure did not emerge as significant predictors of CIP. In addition, trait vulnerability to CIP may also be familial in nature.
doi:10.1016/j.drugalcdep.2009.10.006
PMCID: PMC2821949  PMID: 19944543
cocaine; paranoia; cannabis; adolescent
9.  Cannabis users differ from non-users on measures of personality and schizotypy 
Psychiatry research  2011;186(1):46-52.
Accumulating evidence indicates that cannabis use may be a risk factor for schizophrenia (SZ), and chronic cannabis users score higher than non-users on measures of schizotypal personality traits. The purpose of the present study was to investigate the relations between normal personality, schizotypy, and cannabis use. Sixty-two chronic cannabis users and 45 cannabis-naïve controls completed a measure of normal personality, the NEO-Five Factor Inventory (NEO-FFI), and two measures of schizotypy, the Schizotypal Personality Questionnaire (SPQ) and Perceptual Aberration Scale (PAS). Substance use was assessed using the SCID I alcohol/drug module and a locally developed drug use questionnaire. On the NEO-FFI, users scored higher than controls on Openness, but lower on Agreeableness and Conscientiousness, and endorsed greater schizotypy on the SPQ and PAS. Higher Neuroticism predicted greater schizotypy in both groups, and, higher Extraversion predicted lower negative-syndrome schizotypy among users. Finally, duration of cannabis use was positively correlated with scores on the SPQ and PAS among users, suggesting a relation between overall cannabis use chronicity and schizotypy. These data show that cannabis users differ from non-users on dimensions of normal personality and schizotypy, and provide further evidence that cannabis use is associated with increased levels of psychosis-related personality traits.
doi:10.1016/j.psychres.2010.07.035
PMCID: PMC3036782  PMID: 20813412
Five-factor model; marijuana; Schizotypal Personality Questionnaire; Perceptual Aberration Scale; schizophrenia
10.  DSM-5 Cannabis Use Disorder: A Phenotypic and Genomic Perspective* 
Drug and alcohol dependence  2013;134:362-369.
Background
We explore the factor structure of DSM-5 cannabis use disorders, examine its prevalence across European- and African-American respondents as well as its genetic underpinnings, utilizing data from a genome-wide study of single nucleotide polymorphisms (SNPs). We also estimate the heritability of DSM-5 cannabis use disorders explained by these common SNPs.
Methods
Data on 3053 subjects reporting a lifetime history of cannabis use were utilized. Exploratory and confirmatory factor analyses were conducted to create a factor score, which was used in a genomewide association analysis. P-values from the single SNP analysis were examined for evidence of gene-based association. The aggregate effect of all SNPs was also estimated using Genome-Wide Complex Traits Analysis.
Results
The unidimensionality of DSM-5 cannabis use disorder criteria was demonstrated. Comparing DSM-IV to DSM-5, a decrease in prevalence of cannabis use disorders was only noted in European-American respondents and was exceedingly modest. For the DSM-5 cannabis use disorders factor score, no SNP surpassed the genome-wide significance testing threshold. However, in the European-American subsample, gene-based association testing resulted in significant associations in 3 genes (C17orf58, BPTF and PPM1D) on chromosome 17q24. In aggregate, 21% of the variance in DSM-5 cannabis use disorders was explained by the genomewide SNPs; however, this estimate was not statistically significant.
Conclusions
DSM-5 cannabis use disorder represents a unidimensional construct, the prevalence of which is only modestly elevated above the DSM-IV version. Considerably larger sample sizes will be required to identify individual SNPs associated with cannabis use disorders and unequivocally establish its polygenic underpinnings.
doi:10.1016/j.drugalcdep.2013.11.008
PMCID: PMC3943464  PMID: 24315570
Cannabis; DSM-5; GWAS; association; genetics; heritability
11.  Implicit Associations and Explicit Expectancies toward Cannabis in Heavy Cannabis Users and Controls 
Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations toward cannabis were measured with three Single Category Implicit Association Tests (SC-IAT’s) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive-arousal associations but weaker implicit negative associations toward cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies toward cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users.
doi:10.3389/fpsyt.2013.00059
PMCID: PMC3689035  PMID: 23801968
cannabis; implicit association test; cannabis use disorder; craving; affective associations
12.  Cannabis Receptor Haplotype Associated With Fewer Cannabis Dependence Symptoms In Adolescents 
Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single-nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview- Substance Abuse Module. Univariate (single-marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (p < 0.02). This was consistent with the results of the global haplotype test (p < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.
doi:10.1002/ajmg.b.30378
PMCID: PMC2564870  PMID: 16917946
Cannabis; Adolescence; Genetics; CNR1
13.  Predictors of onset of cannabis and other drug use in male young adults: results from a longitudinal study 
BMC Public Health  2014;14(1):1202.
Background
The use of cannabis and other illegal drugs is particularly prevalent in male young adults and is associated with severe health problems. This longitudinal study explored variables associated with the onset of cannabis use and the onset of illegal drug use other than cannabis separately in male young adults, including demographics, religion and religiosity, health, social context, substance use, and personality. Furthermore, we explored how far the gateway hypothesis and the common liability to addiction model are in line with the resulting prediction models.
Methods
The data were gathered within the Cohort Study on Substance Use Risk Factors (C-SURF). Young men aged around 20 years provided demographic, social, health, substance use, and personality-related data at baseline. Onset of cannabis and other drug use were assessed at 15-months follow-up. Samples of 2,774 and 4,254 individuals who indicated at baseline that they have not used cannabis and other drugs, respectively, in their life and who provided follow-up data were used for the prediction models. Hierarchical logistic stepwise regressions were conducted, in order to identify predictors of the late onset of cannabis and other drug use separately.
Results
Not providing for oneself, having siblings, depressiveness, parental divorce, lower parental knowledge of peers and the whereabouts, peer pressure, very low nicotine dependence, and sensation seeking were positively associated with the onset of cannabis use. Practising religion was negatively associated with the onset of cannabis use. Onset of drug use other than cannabis showed a positive association with depressiveness, antisocial personality disorder, lower parental knowledge of peers and the whereabouts, psychiatric problems of peers, problematic cannabis use, and sensation seeking.
Conclusions
Consideration of the predictor variables identified within this study may help to identify young male adults for whom preventive measures for cannabis or other drug use are most appropriate. The results provide evidence for both the gateway hypothesis and the common liability to addiction model and point to further variables like depressiveness or practising of religion that might influence the onset of drug use.
doi:10.1186/1471-2458-14-1202
PMCID: PMC4247759  PMID: 25416140
Onset; Cannabis; Drug use; Male; Young adults
14.  Linkage analyses of cannabis dependence, craving, and withdrawal in the San Francisco Family Study 
Cannabis is the most widely used illicit drug in the United States. There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. This study's aims were to map susceptibility loci for cannabis use and dependence and two narrower cannabis-related phenotypes of “craving” and “withdrawal” using a family study design. Participants were 2524 adults participating in the University of California San Francisco (UCSF) Family Alcoholism Study. DSM-IV diagnoses of cannabis dependence, as well as indices of cannabis craving and withdrawal, were obtained using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms. Multipoint variance component LOD scores were obtained using SOLAR. Genome-wide significance for linkage (LOD > 3.0) was not found for the DSM-IV cannabis dependence diagnosis, however, linkage analyses of cannabis “craving” and the cannabis withdrawal symptom of “nervous, tense, restless or irritable” revealed five sites with LOD scores over 3.0 on chromosomes 1, 3, 6, 7, 9. These results identify new regions of the genome associated with cannabis use phenotypes as well as corroborate the importance of several chromosome regions highlighted in previous linkage analyses for other substance dependence phenotypes.
doi:10.1002/ajmg.b.31050
PMCID: PMC2940710  PMID: 19937978
dependence; genome scan; heritability; marijuana
15.  Association between cannabis use, psychosis, and schizotypal personality disorder: findings from the National Epidemiologic Survey of Alcohol and Related Conditions 
Schizophrenia research  2013;151(0):10.1016/j.schres.2013.10.018.
Background
Studies to date showing an association between cannabis use and schizophrenia-spectrum disorders are of relatively small sample sizes with limitations in generalizability. The present study addresses this gap by examining the relationship between cannabis use and psychotic-like symptoms in a large representative community sample.
Method
Data were derived from the 2004 – 2005 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, Wave 2), a large, nationally representative sample of 34 653 adults from the United States population. We evaluated the association between lifetime cannabis use, psychosis, and schizotypal personality features.
Results
The prevalence of psychosis and schizotypal personality disorder increased significantly with greater cannabis use in a dose-dependent manner. The association between cannabis use and psychosis was 1.27 (95% CI 1.03–1.57) for lifetime cannabis use, 1.79 (95% CI 1.35–2.38) for lifetime cannabis abuse, and 3.69 (95% CI 2.49–5.47) for lifetime cannabis dependence. There was a similar dose-response relationship between the extent of cannabis use and schizotypal personality disorder (OR = 2.02 for lifetime cannabis use, 95% CI 1.69–2.42; OR = 2.83 for lifetime cannabis abuse, 95% CI 2.33–2.43; OR = 7.32 for lifetime cannabis dependence, 95% CI 5.51–9.72). Likelihood of individual schizotypal features increased significantly with increased extent of cannabis use in a dose-dependent manner.
Conclusion
This is the first population-based study to examine the association between lifetime cannabis use, psychosis, and schizotypal personality traits. These results add to evidence that cannabis use may be a risk factor for psychosis liability.
doi:10.1016/j.schres.2013.10.018
PMCID: PMC3877688  PMID: 24200416
cannabis; epidemiology; psychosis; schizotypal; NESARC
16.  Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study 
BMJ : British Medical Journal  2002;325(7374):1199.
Objectives
An association between use of cannabis in adolescence and subsequent risk of schizophrenia was previously reported in a follow up of Swedish conscripts. Arguments were raised that this association may be due to use of drugs other than cannabis and that personality traits may have confounded results. We performed a further analysis of this cohort to address these uncertainties while extending the follow up period to identify additional cases.
Design
Historical cohort study.
Setting
1969-70 survey of Swedish conscripts (>97% of the country's male population aged 18-20).
Participants
50 087 subjects: data were available on self reported use of cannabis and other drugs, and on several social and psychological characteristics.
Main outcome measures
Admissions to hospital for ICD-8/9 schizophrenia and other psychoses, as determined by record linkage.
Results
Cannabis was associated with an increased risk of developing schizophrenia in a dose dependent fashion both for subjects who had ever used cannabis (adjusted odds ratio for linear trend of increasing frequency 1.2, 95% confidence interval 1.1 to 1.4, P<0.001), and for subjects who had used only cannabis and no other drugs (adjusted odds ratio for linear trend 1.3, 1.1 to 1.5, P<0.015). The adjusted odds ratio for using cannabis >50 times was 6.7 (2.1 to 21.7) in the cannabis only group. Similar results were obtained when analysis was restricted to subjects developing schizophrenia after five years after conscription, to exclude prodromal cases.
Conclusions
Cannabis use is associated with an increased risk of developing schizophrenia, consistent with a causal relation. This association is not explained by use of other psychoactive drugs or personality traits relating to social integration.
What is already known about this topicUse of cannabis has been associated with an increased risk of developing schizophreniaAlternative explanations for this association include confounding by personality or by use of other drugs such as amphetamines, and use of cannabis as a form of self medication secondary to the disorderWhat this study addsSelf reported cannabis use is associated with an increased risk of subsequently developing schizophrenia, consistent with a causal relationThis association is not explained by sociability personality traits, or by use of amphetamines or other drugsSelf medication with cannabis is an unlikely explanation for the association observed
PMCID: PMC135490  PMID: 12446534
17.  Stromal mesenchyme cell genes of the human prostate and bladder 
BMC Urology  2005;5:17.
Background
Stromal mesenchyme cells play an important role in epithelial differentiation and likely in cancer as well. Induction of epithelial differentiation is organ-specific, and the genes responsible could be identified through a comparative genomic analysis of the stromal cells from two different organs. These genes might be aberrantly expressed in cancer since cancer could be viewed as due to a defect in stromal signaling. We propose to identify the prostate stromal genes by analysis of differentially expressed genes between prostate and bladder stromal cells, and to examine their expression in prostate cancer.
Methods
Immunohistochemistry using antibodies to cluster designation (CD) cell surface antigens was first used to characterize the stromas of the prostate and bladder. Stromal cells were prepared from either prostate or bladder tissue for cell culture. RNA was isolated from the cultured cells and analyzed by DNA microarrays. Expression of candidate genes in normal prostate and prostate cancer was examined by RT-PCR.
Results
The bladder stroma was phenotypically different from that of the prostate. Most notable was the presence of a layer of CD13+ cells adjacent to the urothelium. This structural feature was also seen in the mouse bladder. The prostate stroma was uniformly CD13-. A number of differentially expressed genes between prostate and bladder stromal cells were identified. One prostate gene, proenkephalin (PENK), was of interest because it encodes a hormone. Secreted proteins such as hormones and bioactive peptides are known to mediate cell-cell signaling. Prostate stromal expression of PENK was verified by an antibody raised against a PENK peptide, by RT-PCR analysis of laser-capture microdissected stromal cells, and by database analysis. Gene expression analysis showed that PENK expression was down-regulated in prostate cancer.
Conclusion
Our findings show that the histologically similar stromas of the prostate and bladder are phenotypically different, and express organ-specific genes. The importance of these genes in epithelial development is suggested by their abnormal expression in cancer. Among the candidates is the hormone PENK and the down-regulation of PENK expression in cancer suggests a possible association with cancer development.
doi:10.1186/1471-2490-5-17
PMCID: PMC1327674  PMID: 16343351
18.  The association between cannabis abuse and dependence and childhood physical and sexual abuse: Evidence from an offspring of twins design 
Addiction (Abingdon, England)  2008;103(6):990-997.
Aims
This study examines the association between childhood physical abuse (CPA) and sexual abuse (CSA) and the development of cannabis abuse and dependence among adolescents and young adults while controlling for genetic and environmental risk factors.
Design
To control for familial risk differences related to paternal drug dependence that might confound the relationship between CSA and CPA and cannabis abuse/dependence, we created four groups based on father’s and uncle’s substance use dependence (SUD) status reflecting different degrees of genetic and environmental risks to offspring: 1) high genetic, high environmental risk; 2) high genetic, low environmental risk, 3) medium genetic, low environmental risk; and 4) low genetic, low environmental risk.
Participants
Adolescent and young adult offspring of monozygotic and dizygotic US military veteran twin fathers (n= 819).
Measurements
Data on CPA and CSA, DSM-IV offspring cannabis abuse/dependence, other SUD and psychopathology, and maternal and paternal SUD and psychopathology were collected via semi-structured telephone interview.
Findings
Twenty-three percent of the offspring sample met lifetime criteria for cannabis abuse/dependence, 8.55% and 12.82% reported CSA and CPA, respectively. Offspring exposed to CSA, but not CPA, were at significantly greater risk of developing cannabis abuse/dependence compared to those who had not experienced CSA (HR=2.16; 95% CI=1.48–3.16) after controlling for genetic and familial environmental risk and offspring gender, alcohol abuse and dependence and conduct disorder.
Conclusions
These results indicate that there are effects of CSA on development of cannabis abuse/dependence in addition to the genetic and familial environmental risk imparted by having a drug dependent father.
doi:10.1111/j.1360-0443.2008.02210.x
PMCID: PMC2653098  PMID: 18482422
physical abuse; sexual abuse; cannabis abuse and dependence; offspring of twins
19.  Common Genetic Contributions to Alcohol and Cannabis Use and Dependence Symptomatology 
Background
Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the two substances has only rarely been explored. In the current study, we quantified cross-substance overlap in sources of variance and estimated the degree to which within-substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis.
Methods
The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 736 singletons) from the Australian Twin Registry, aged 24-36 years. Alcohol and cannabis use histories were collected via telephone diagnostic interviews and used to derive an alcohol consumption factor, a frequency measure for cannabis use, and DSM-IV alcohol and cannabis dependence symptom counts. Standard genetic analyses were conducted to produce a quadrivariate model that provided estimates of overlap in genetic and environmental influences across the four phenotypes.
Results
Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the four phenotypes. Nearly complete overlap in heritable influences was observed for within-substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively.
Conclusions
Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance-specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability for alcohol- and cannabis-related problems as dependence symptomatology.
doi:10.1111/j.1530-0277.2009.01120.x
PMCID: PMC3089946  PMID: 20028363
alcohol dependence; cannabis dependence; genetics; twins
20.  COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users 
Neuropsychopharmacology  2013;38(8):1598-1606.
The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions.
doi:10.1038/npp.2013.59
PMCID: PMC3682154  PMID: 23449176
Addiction & Substance Abuse; Cannabinoids; cannabis; Cognition; executive functions; genes; Neurogenetics; cannabis; COMT; decision making; serotonin; shifting; sustained attention
21.  Cannabis Withdrawal is Common among Treatment-Seeking Adolescents with Cannabis Dependence and Major Depression, and is Associated with Rapid Relapse to Dependence 
Addictive behaviors  2008;33(11):1500-1505.
Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. We hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence.
doi:10.1016/j.addbeh.2008.02.001
PMCID: PMC2565493  PMID: 18313860
22.  Effectiveness of a Self-Guided Web-Based Cannabis Treatment Program: Randomized Controlled Trial 
Background
Self-help strategies offer a promising way to address problems with access to and stigma associated with face-to-face drug and alcohol treatment, and the Internet provides an excellent delivery mode for such strategies. To date, no study has tested the effectiveness of a fully self-guided web-based treatment for cannabis use and related problems.
Objectives
The current study was a two-armed randomized controlled trial aimed at testing the effectiveness of Reduce Your Use, a fully self-guided web-based treatment program for cannabis use disorder consisting of 6 modules based on cognitive, motivational, and behavioral principles.
Methods
225 individuals who wanted to cease or reduce their cannabis use were recruited using both online and offline advertising methods and were randomly assigned to receive: (1) the web-based intervention, or (2) a control condition consisting of 6 modules of web-based educational information on cannabis. Assessments of cannabis use, dependence symptoms, and abuse symptoms were conducted through online questionnaires at baseline, and at 6-week and 3-month follow-ups. Two sets of data analyses were undertaken—complier average causal effect (CACE) modeling and intention to treat (ITT).
Results
Two thirds (149) of the participants completed the 6-week postintervention assessment, while 122 (54%) completed the 3-month follow-up assessment. Participants in the intervention group completed an average of 3.5 of the 6 modules. The CACE analysis revealed that at 6 weeks, the experimental group reported significantly fewer days of cannabis use during the past month (P=.02), significantly lower past-month quantity of cannabis use (P=.01), and significantly fewer symptoms of cannabis abuse (P=.047) relative to controls. Cannabis dependence symptoms (number and severity) and past-month abstinence did not differ significantly between groups (Ps>.05). Findings at 3 months were similar, except that the experimental group reported significantly fewer and less severe cannabis dependence symptoms (Ps<.05), and past-month quantity of cannabis consumed no longer differed significantly between groups (P=.16). ITT analyses yielded similar outcomes.
Conclusion
Findings suggest that web-based interventions may be an effective means of treating uncomplicated cannabis use and related problems and reducing the public health burden of cannabis use disorders.
Trial registration
ACTRN12609000856213, Australian New Zealand Clinical Trials Registry.
doi:10.2196/jmir.2256
PMCID: PMC3636012  PMID: 23470329
marijuana; Internet intervention; computer-assisted therapy; addiction; randomized controlled trial
23.  Prefrontal Dopaminergic and Enkephalinergic Synaptic Accommodation in HIV-associated Neurocognitive Disorders and Encephalitis 
Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression. Conclusion: Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.
doi:10.1007/s11481-012-9345-4
PMCID: PMC3419353  PMID: 22391864
Dopamine receptor; Enkephalin; HAND; HIVE; HIV encephalitis; HIV-associated neurocognitive disorders; Interferon regulatory factor; Opiate; Opioid; Synaptic plasticity
24.  The Association between Cannabinoid Receptor 1 Gene (CNR1) and Cannabis Dependence Symptoms in Adolescents and Young Adults 
Drug and alcohol dependence  2009;104(1-2):11-16.
Objective:
This study examined the genetic association between variation in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence symptoms.
Method:
Adolescent and young adult subjects were recruited from three settings: a treatment program for youth with substance use disorders, the criminal justice system, and the community. A case-control sample consisted of 224 cases who endorsed at least one dependence symptom and 108 controls who tried cannabis but endorsed no symptoms. A family-based sample of 219 families was also analyzed.
Results:
Case-control analysis identified a nominal association between SNP rs1049353 and having one or more cannabis dependence symptoms (p = .029), but the association did not hold up in a combined sample. Family-based analysis found a trend for the same SNP (p = .07). We did not replicate a previous report that SNP rs806380 was associated with the development of cannabis dependence.
Conclusion:
These results provide inconclusive evidence of association between rs1049353/rs806380 and the development of cannabis dependence, and underscore the importance of replicating results of genetic association studies. Additional family-based studies are needed to clarify the role of the CNR1 gene, and its various SNPs, in the development of cannabis use disorders.
doi:10.1016/j.drugalcdep.2009.01.022
PMCID: PMC2769509  PMID: 19443135
cannabis dependence; CNR1; genetic association; cannabinoids
25.  Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens 
Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.
doi:10.3389/fnbeh.2014.00388
PMCID: PMC4220701  PMID: 25414651
maternal; bonding; reward; addiction; genes; enrichment; nucleus accumbens

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