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1.  A Genome-Wide Scan for Loci Influencing Adolescent Cannabis Dependence Symptoms: Evidence for Linkage on Chromosomes 3 and 9 
Drug and alcohol dependence  2006;89(1):34-41.
Objective:
Cannabis is the most frequently abused illicit substance among adolescents and young adults. Genetic risk factors account for part of the variation in the development of Cannabis Dependence symptoms; however, no linkage studies have been performed for Cannabis Dependence symptoms. This study aimed to identify such loci.
Method:
324 sibling pairs from 192 families were assessed for Cannabis Dependence symptoms. Probands (13-19 years of age) were recruited from consecutive admissions to substance abuse treatment facilities. The siblings of the probands ranged in age from 12-25 years. A community-based sample of 4843 adolescents and young adults was utilized to define an age- and sex-corrected index of Cannabis Dependence vulnerability. DSM-IV Cannabis Dependence symptoms were assessed in youth and their family members with the Composite International Diagnostic Instrument -Substance Abuse Module. Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (average inter-marker distance = 9.2 cM). Cannabis Dependence symptoms were analyzed using Merlin-regress, a regression-based method that is robust to sample selection.
Results:
Evidence for suggestive linkage was found on chromosome 3q21 near marker D3S1267 (LOD = 2.61), and on chromosome 9q34 near marker D9S1826 (LOD = 2.57).
Conclusions:
This is the first reported linkage study of cannabis dependence symptoms. Other reports of linkage regions for illicit substance dependence have been reported near 3q21, suggesting that this region may contain a quantitative trait loci influencing cannabis dependence and other substance use disorders.
doi:10.1016/j.drugalcdep.2006.11.015
PMCID: PMC1892279  PMID: 17169504
genetics; Cannabis; antisocial behavior; adolescence; linkage study
2.  The Role of Study and Work in Cannabis Use and Dependence Trajectories among Young Adult Frequent Cannabis Users 
Life course theory considers events in study and work as potential turning points in deviance, including illicit drug use. This qualitative study explores the role of occupational life in cannabis use and dependence in young adults. Two and three years after the initial structured interview, 47 at baseline frequent cannabis users were interviewed in-depth about the dynamics underlying changes in their cannabis use and dependence. Overall, cannabis use and dependence declined, including interviewees who quit using cannabis completely, in particular with students, both during their study and after they got employed. Life course theory appeared to be a useful framework to explore how and why occupational life is related to cannabis use and dependence over time. Our study showed that life events in this realm are rather common in young adults and can have a strong impact on cannabis use. While sometimes changes in use are temporary, turning points can evolve from changes in educational and employment situations; an effect that seems to be related to the consequences of these changes in terms of amount of leisure time and agency (i.e., feelings of being in control).
doi:10.3389/fpsyt.2013.00085
PMCID: PMC3739012  PMID: 23950748
frequent cannabis use; cannabis dependence; young adults; qualitative research; life course approach; longitudinal study; education; employment
3.  A Preliminary Trial: Double-Blind Comparison of Nefazodone, Bupropion-SR and Placebo in the Treatment of Cannabis Dependence 
The present study investigated the efficacy of nefazodone and bupropion-sustained release for treating cannabis dependence. A double blind, placebo controlled, piggy back design was employed to assess if nefazodone and bupropion-sustained release increased the probability of abstinence from cannabis and reduced the severity of cannabis dependence and cannabis withdrawal symptoms during a 13-week outpatient treatment program. One-hundred and six participants (M=32 years; Females n=25) were randomized to one of three medication conditions (nefazodone, bupropion-sustained release, or placebo) and participated in a weekly individually based coping skills therapy program. Results indicated a an increased probability of achieving abstinence over the course of treatment and a decrease in the severity of cannabis dependence and the withdrawal symptom of irritability. There were no significant effects demonstrated for nefazodone and bupropion-sustained release on cannabis use or cannabis withdrawal symptoms. The results indicate nefazodone and bupropion-sustained release may have limited efficacy in treating cannabis dependence.
doi:10.1080/10550490802408936
PMCID: PMC2759381  PMID: 19219666
Nefazodone; Bupropion; cannabis dependence; marijuana dependence
4.  Quantifying the Clinical Significance of Cannabis Withdrawal 
PLoS ONE  2012;7(9):e44864.
Background and Aims
Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.
Methods and Results
A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001).
Conclusions
Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes.
doi:10.1371/journal.pone.0044864
PMCID: PMC3458862  PMID: 23049760
5.  Negative consequences associated with dependence in daily cannabis users 
Background
Cannabis is the most widely consumed illicit substance in America, with increasing rates of use. Some theorists tend to link frequency of use with cannabis dependence. Nevertheless, fewer than half of daily cannabis users meet DSM-IV-TR criteria for cannabis dependence. This study seeks to determine whether the negative aspects associated with cannabis use can be explained by a proxy measure of dependence instead of by frequency of use.
Results
Over 2500 adult daily cannabis users completed an Internet survey consisting of measures of cannabis and other drug use, in addition to measures of commonly reported negative problems resulting from cannabis use. We compared those who met a proxy measure of DSM-IV-TR criteria for cannabis dependence (N = 1111) to those who did not meet the criteria (N = 1770). Cannabis dependent subjects consumed greater amounts of cannabis, alcohol, and a variety of other drugs. They also had lower levels of motivation, happiness, and satisfaction with life, with higher levels of depression and respiratory symptoms.
Conclusion
Although all of our subjects reported daily use, only those meeting proxy criteria for cannabis dependence reported significant associated problems. Our data suggest that dependence need not arise from daily use, but consuming larger amounts of cannabis and other drugs undoubtedly increases problems.
doi:10.1186/1747-597X-2-3
PMCID: PMC1783648  PMID: 17214886
6.  12-month follow-up of an exploratory ‘brief intervention’ for high-frequency cannabis users among Canadian university students 
Background
One in three young people use cannabis in Canada. Cannabis use can be associated with a variety of health problems which occur primarily among intensive/frequent users. Availability and effectiveness of conventional treatment for cannabis use is limited. While Brief Interventions (BIs) have been shown to result in short-term reductions of cannabis use risks or problems, few studies have assessed their longer-term effects. The present study examined 12-month follow-up outcomes for BIs in a cohort of young Canadian high-frequency cannabis users where select short-term effects (3 months) had previously been assessed and demonstrated.
Findings
N = 134 frequent cannabis users were recruited from among university students in Toronto, randomized to either an oral or a written cannabis BI, or corresponding health controls, and assessed in-person at baseline, 3-months, and 12-months. N = 72 (54 %) of the original sample were retained for follow-up analyses at 12-months where reductions in ‘deep inhalation/breathholding’ (Q = 13.1; p < .05) and ‘driving after cannabis use’ (Q = 9.3; p < .05) were observed in the experimental groups. Reductions for these indicators had been shown at 3-months in the experimental groups; these reductions were maintained over the year. Other indicators assessed remained overall stable in both experimental and control groups.
Conclusions
The results confirm findings from select other studies indicating the potential for longer-term and sustained risk reduction effects of BIs for cannabis use. While further research is needed on the long-term effects of BIs, these may be a valuable – and efficient – intervention tool in a public health approach to high-risk cannabis use.
doi:10.1186/1747-597X-7-15
PMCID: PMC3504513  PMID: 22538183
Cannabis use; Frequent use; Young adults; Brief interventions; Prevention; Canada
7.  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
8.  Pharmacological Treatment of Cannabis Dependence 
Current pharmaceutical design  2011;17(14):1351-1358.
Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability), those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA). Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications.
PMCID: PMC3171994  PMID: 21524266
Cannabis; withdrawal; dependence; pharmacotherapy; treatment
9.  Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers 
Molecular Psychiatry  2011;17(6):642-649.
Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ~4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.
doi:10.1038/mp.2011.82
PMCID: PMC3223558  PMID: 21747398
addiction; cannabis; CB1 receptor; positron emission tomography; receptor imaging
10.  Cannabis withdrawal in chronic cannabis users with schizophrenia 
Journal of psychiatric research  2012;47(2):240-245.
Background
Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia.
Methods
Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire.
Results
120 participants, predominantly African–American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8–48]) preceded their age at first psychotic symptoms (20 [4–50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use.
Conclusion
Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.
doi:10.1016/j.jpsychires.2012.10.010
PMCID: PMC3591813  PMID: 23146560
Schizophrenia; Marijuana; Co-morbidity; Cannabis; Withdrawal
11.  A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults 
Neuropsychopharmacology  2012;37(7):1689-1698.
There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18–65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis–Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.
doi:10.1038/npp.2012.14
PMCID: PMC3358737  PMID: 22373942
cannabis dependence; marijuana withdrawal; executive function; gabapentin; addiction treatment; randomized controlled trial; addiction & substance abuse; GABA; clinical pharmacology/clinical trials; psychopharmacology; cannabis dependence; marijuana withdrawal; executive function; gabapentin; addiction treatment; controlled trial
12.  Frequent alcohol, nicotine or cannabis use is common in young persons presenting for mental healthcare: a cross-sectional study 
BMJ Open  2013;3(2):e002229.
Objectives
To determine the prevalence of recent alcohol, nicotine or cannabis use in young persons presenting for mental healthcare.
Design
A cross-sectional study of young people seeking mental healthcare completed self-report questionnaires regarding their use of alcohol, nicotine or cannabis.
Setting
Data were collected from two sites as part of the national headspace services programme.
Participants
2122 young people aged 12–30 years provided information as part of a patient register; a subset of N=522 participants also provided more detailed information about their patterns of alcohol use.
Outcome measures
Prevalence levels of recent alcohol, nicotine or cannabis use within relevant age bands (12–17, 18–19 and 20–30) or primary diagnostic categories.
Results
The rates for use at least weekly of alcohol for the three age bands were 12%, 39% and 45%, and for cannabis 7%, 14% and 18%, respectively. The rates of daily nicotine use for the three age bands were 23%, 36% and 41%. The pattern of alcohol use was characterised by few abstainers as well as many risky drinkers. Age of onset across all three substances was approximately 15 years. Individuals who used any of the three substances more frequently were likely to be older, male or have psychotic or bipolar disorders.
Conclusions
Frequent use of alcohol, nicotine or cannabis in young people seeking mental healthcare is common. Given the restricted legal access, the patterns of use in those aged 12–17 years are particularly notable. Reductions in substance use needs to be prioritised within services for at-risk young people.
doi:10.1136/bmjopen-2012-002229
PMCID: PMC3586076  PMID: 23381649
Alcohol; Depression; Mental Health; Psychiatry
13.  Cannabis abuse and brain morphology in schizophrenia: a review of the available evidence 
Substance abuse is the most prevalent comorbid psychiatric condition associated with schizophrenia, and cannabis is the illicit drug most often abused. Apart from worsening the course of schizophrenia, frequent cannabis use especially at an early age seems to be an important risk factor for developing schizophrenia. Although a large body of neuroimaging studies gives evidence for structural alterations in many different brain regions in schizophrenia patients, there is still limited knowledge of the impact of cannabis abuse on brain structure in schizophrenia. We performed a systematic review including structural magnetic resonance imaging studies comparing high-risk and schizophrenia patients with and without cannabis abuse and found inconclusive results. While there is some evidence that chronic cannabis abuse could alter brain morphology in schizophrenia in patients continuing their cannabis consumption, there is no convincing evidence that this alteration takes place before the onset of schizophrenia when looking at first-episode patients. There is some weak evidence that cannabis abuse could affect brain structures in high-risk subjects, but replication of these studies is needed.
doi:10.1007/s00406-012-0346-3
PMCID: PMC3560946  PMID: 22907121
Cannabis; Substance abuse; Magnetic resonance imaging; Schizophrenia; High-risk subjects; First-episode patients
14.  An Item Response Theory Analysis of DSM-IV Cannabis Abuse and Dependence Criteria in Adolescents 
Objective
To examine three aspects of adolescent cannabis problems: 1) do DSM-IV cannabis abuse and dependence criteria represent two different levels of severity of substance involvement, 2) to what degree do each of the 11 abuse and dependence criteria assess adolescent cannabis problems, and 3) do the DSM-IV items function similarly across different adolescent populations?
Method
We examined 5587 adolescents aged 11–19, including 615 youth in treatment for substance use disorders, 179 adjudicated youth, and 4793 youth from the community. All subjects were assessed with a structured diagnostic interview. Item response theory was utilized to analyze symptom endorsement patterns.
Results
Abuse and dependence criteria were not found to represent different levels of severity of problem cannabis use in any of the samples. Among the 11 abuse and dependence criteria, Problems cutting down and Legal problems were the least informative for distinguishing problem users. Two dependence criteria and three of the four abuse criteria indicated different severities of cannabis problems across samples.
Conclusions
We found little evidence to support the idea that abuse and dependence are separate constructs for adolescent cannabis problems. Furthermore, certain abuse criteria may indicate severe substance problems while specific dependence items may indicate less severe problems. The abuse items in particular need further study. These results have implications for the refinement of the current substance use disorder criteria for DSM-V.
doi:10.1097/chi.0b013e31815cd9f2
PMCID: PMC2443687  PMID: 18176333
Item Response Theory; cannabis abuse; cannabis dependence; DSM-IV; DSM-V
15.  An exploratory study of cannabis withdrawal among Indigenous Australian prison inmates: study protocol 
BMJ Open  2013;3(5):e002951.
Introduction
Cannabis use and dependence is a serious health and criminal justice issue among incarcerated populations internationally. Upon abrupt, enforced cessation of cannabis, prisoners may suffer irritability and anger that can lead to threatening behaviour, intimidation, violence, sleep disturbances and self-harm. Cannabis withdrawal syndrome, proposed for inclusion in the Diagnostic and Statistical Manual of Mental Disorders in 2013, has not been examined in Indigenous populations. Owing to the exceptionally high rates of cannabis use in the community, high proportions of Australian Indigenous prisoners may suffer from withdrawal upon entry to custody.
Methods and analysis
60 male and 60 female Indigenous prisoners (18–40 years) at a high risk of cannabis dependence will be recruited upon entry to custody. A pictorial representation of the standard Cannabis Withdrawal Scale will be tested for reliability and validity. Cortisol markers will be measured in saliva, as the indicators of onset and severity of cannabis withdrawal and psychological distress. The characteristics will be described as percentages and mean or median values with 95% CI. Receiver operator curve analysis will determine an ideal cut-off of the Cannabis Withdrawal Scale and generalised estimating equations modelling will test changes over time. The acceptability and efficacy of proposed resources will be assessed qualitatively using thematic analysis.
Outcomes
A valid and reliable measure of cannabis withdrawal for use with Indigenous populations, the onset and time course of withdrawal symptoms in this population and the development of culturally acceptable resources and interventions to identify and manage cannabis withdrawal.
Ethics and dissemination
The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4651).The results will be reported via peer reviewed publications, conference, seminar presentations and on-line media for national and international dissemination.
doi:10.1136/bmjopen-2013-002951
PMCID: PMC3657653  PMID: 23793690
Substance Withdrawal Syndrome; Cannabis; Indigenous; Australia; Prisoners
16.  Longitudinal Modeling of Transmissible Risk in Boys Who Subsequently Develop Cannabis Use Disorder 
Background
Risk for substance use disorder is frequently transmitted across generations due to significant heritability.
Objective
This longitudinal study tests the hypothesis that initial exposure to cannabis in youths having high transmissible risk is a signal event promoting development of cannabis use disorder (CUD).
Methods
At age 22, 412 men were classified into three groups: (1) lifetime CUD, (2) cannabis use without CUD, and (3) no lifetime cannabis use. Transmissible risk, quantified on a continuous scale using the previously validated transmissible liability index (TLI), along with cannabis use and CUD were documented at 10–12, 12–14, 16, 19, and 22 years of age.
Results
The CUD group scored higher on the TLI before they began cannabis use compared to the other two groups. In addition, a progressive increase in TLI severity was evinced by the CUD group beginning at the time of initiation of cannabis use whereas cannabis users who did not subsequently develop CUD exhibited a decline in transmissible risk following first exposure.
Conclusion
Initial use of cannabis potentiates development of CUD in youths who are at high transmissible risk but is inconsequential in youths having low risk. The practical ramifications of these results for prevention are discussed.
doi:10.3109/00952990.2013.774009
PMCID: PMC3752787  PMID: 23721533
Transmissible Liability; Addiction; Cannabis use disorder; Longitudinal modeling
17.  Patterns of use, sequence of onsets and correlates of tobacco and cannabis 
Addictive behaviors  2011;36(12):1141-1147.
Background
While most individuals initiate their use of tobacco prior to onset of cannabis use, recent reports have identified a smaller subset of youth who report onset of cannabis use prior to tobacco use. In this study, we characterize patterns of cannabis and tobacco use (tobacco but not cannabis, cannabis but not tobacco or both) and compare the factors associated with onset of tobacco before cannabis and cannabis before tobacco.
Methods
Data on 1812 offspring aged 12–32 years, drawn from two related offspring of Vietnam Era twin studies, were used. Individuals were divided into tobacco but not cannabis (T), cannabis but not tobacco (C) and users of both substances (CT). Those who used both could be further classified by the timing of onset of tobacco and cannabis use. Multinomial logistic regression was used to characterize the groups using socio-demographic and psychiatric covariates. Furthermore, data on parental smoking and drug use was used to identify whether certain groups represented greater genetic or environmental vulnerability.
Results
22% (n=398) reported T, 3% (n=55) reported C and 44% reported CT (n=801). Of the 801 CT individuals, 72.8% (n=583), 9.9% (n=77) and 17.3% (n=139) reported onset of tobacco before cannabis, cannabis before tobacco and onsets at the same age. C users were as likely as CT users to report peer drug use and psychopathology, such as conduct problems while CT was associated with increased tobacco use relative to T. Onset of tobacco prior to cannabis, when compared onset of cannabis before tobacco or reporting initiation at the same age was associated with greater cigarettes smoked per day, however no distinct factors distinguished the group with onset of cannabis before tobacco from those with initiation at the same age.
Conclusion
A small subset of individuals report cannabis without tobacco use. Of those who use both cannabis and tobacco, a small group report cannabis use prior to tobacco use. Follow-up analyses that chart the trajectories of these individuals will be required to delineate their course of substance involvement.
doi:10.1016/j.addbeh.2011.07.005
PMCID: PMC3183489  PMID: 21820810
Cannabis; Tobacco; Reverse Gateways
18.  Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization 
The American journal of psychiatry  2010;167(8):987-993.
Objective
The authors examined the relationship between cannabis use and the course of illness in schizophrenia over 10 years following first psychiatric hospitalization.
Method
We assessed 229 patients with a schizophrenia-spectrum disorder five times: during the first admission, and 6 months, 2 years, 4 years, and 10 years later. Ratings of cannabis use and psychiatric symptoms (psychotic, negative, disorganized, and depressive) were made at each assessment.
Results
The lifetime rate of cannabis use was 66.2%, and survival analysis revealed that this usage was associated with an earlier onset of psychosis. The rates of current use ranged from 10% to 18% across assessments. Cannabis status was moderately stable, with concordance between waves ranging rtet = 0.48 – 0.78. Mixed-effects logistic regression revealed that changes in cannabis use were associated with changes in psychotic symptoms over time even after gender, age, socio-economic status, other drug use, antipsychotic medication use, and other symptoms were controlled. Structural equation modeling indicated that the association with psychotic symptoms was bi-directional.
Conclusions
Cannabis use is associated with an adverse course of psychotic symptoms in schizophrenia, and vice versa, even after taking into account other clinical, substance, and demographic variables. The specificity of this relationship suggests that clinical interventions to reduce cannabis use may be best targeted at individuals with prominent psychotic symptoms.
doi:10.1176/appi.ajp.2010.09020189
PMCID: PMC3594105  PMID: 20478874
19.  The Role of Cannabis Use Within a Dimensional Approach to Cannabis Use Disorders 
Drug and alcohol dependence  2008;100(3):221-227.
Context
Cannabis consumption is central to diagnosis of DSM-IV cannabis abuse and dependence; yet, most research on cannabis disorders has focused just on diagnosis or criteria. The present study examines the ability of a frequency and quantity measure of cannabis use as well as cannabis abuse and dependence criteria to discriminate between individuals across the cannabis use disorder continuum.
Method
A representative sample of USA adults in 2001–2002 (N=43,093) were queried about past year frequency of cannabis use and each DSM-IV cannabis abuse and dependence criterion. Factor analysis and item response theory (IRT) models were used to define the relationship between observed responses and the underlying unobserved latent trait (cannabis use disorder severity).
Results
Factor analyses demonstrated a good fit for a one factor model both with and without the cannabis use criterion and no differential criterion functioning was demonstrated across sex. The IRT model including the cannabis use criterion had discriminatory power comparable to the model without the cannabis use criterion and exceeded the informational value of the model without the cannabis use criterion in mild and moderate ranges of the severity continuum.
Discussion
Factor and IRT analyses disprove the validity of the DSM-IV abuse and dependence distinction: A single dimension represented the criteria rather than the two implied by the separate abuse/dependence categories. IRT models identified some dependence criteria to be among the mildest and some abuse criteria to be among the most severe —results inconsistent with the interpretation of DSM-IV cannabis abuse as a milder disorder or prodrome of cannabis dependence. The consumption criterion defined the mild end of the cannabis use disorder continuum and its excellent psychometric properties strongly supported its inclusion as a DSM -V criterion for cannabis use disorders. Additional work is needed to identify candidate consumption criteria across all drugs that apply to the milder end of the severity continuum while also improving overall model performance and clinical diagnostic utility.
doi:10.1016/j.drugalcdep.2008.10.009
PMCID: PMC3153503  PMID: 19062204
Cannabis use disorders; IRT analysis; Cannabis use
20.  Sociodemographic Characteristics of Cannabis Smokers and the Experience of Cannabis Withdrawal 
Background
Cannabis withdrawal can be a negative reinforcer for relapse, but little is known about its association with demographic characteristics.
Objectives
Evaluate the association of demographic characteristics with the experience of cannabis withdrawal.
Methods
Retrospective self-report of a “serious” cannabis quit attempt without formal treatment in a convenience sample of 104 non-treatment-seeking, adult cannabis smokers (mean age 35 years, 52% white, 78% male) with no other current substance use disorder (except tobacco) or chronic health problems. Reasons for quitting, coping strategies to help quit, and 18 specific withdrawal symptoms were assessed by questionaire.
Results
Among withdrawal symptoms, only anxiety, increased sex drive, and craving showed significant associations with age, race, or sex. Women were more likely than men to report a physical withdrawal symptom (OR = 3.2, 95% CI = .99–10.4, p = .05), especially upset stomach. There were few significant demographic associations with coping strategies or reasons for quitting.
Conclusions and Scientific Significance
This small study suggests that there are few robust associations between demographic characteristics and cannabis withdrawal. Future studies with larger samples are needed. Attention to physical withdrawal symptoms in women may help promote abstinence.
doi:10.3109/00952990.2010.503825
PMCID: PMC3197209  PMID: 20678028
Age; cannabis; marijuana; quitting; race; relapse; sex; withdrawal
21.  Cannabis Smoking and Periodontal Disease Among Young Adults 
Context
Tobacco smoking is a recognized behavioral risk factor for periodontal disease (through its systemic effects), and cannabis smoking may contribute in a similar way.
Objective
To determine whether cannabis smoking is a risk factor for periodontal disease.
Design and Setting
Prospective cohort study of the general population, with cannabis use determined at ages 18, 21, 26, and 32 years and dental examinations conducted at ages 26 and 32 years. The most recent data collection (at age 32 years) was completed in June 2005.
Participants
A complete birth cohort born in 1972 and 1973 in Dunedin, New Zealand, and assessed periodically (with a 96% follow-up rate of the 1015 participants who survived to age 32 years). Complete data for this analysis were available from 903 participants (comprising 89.0% of the surviving birth cohort).
Main Outcome Measure
Periodontal disease status at age 32 years (and changes from ages 26 to 32 years) determined from periodontal combined attachment loss (CAL) measured at 3 sites per tooth.
Results
Three cannabis exposure groups were determined: no exposure (293 individuals, or 32.3%), some exposure (428; 47.4%), and high exposure (182; 20.2%). At age 32 years, 265 participants (29.3%) had 1 or more sites with 4 mm or greater CAL, and 111 participants (12.3%) had 1 or more sites with 5 mm or greater CAL. Incident attachment loss between the ages of 26 and 32 years in the none, some, and high cannabis exposure groups was 6.5%, 11.2%, and 23.6%, respectively. After controlling for tobacco smoking (measured in pack-years), sex, irregular use of dental services, and dental plaque, the relative risk estimates for the highest cannabis exposure group were as follows: 1.6 (95% confidence interval [CI], 1.2–2.2) for having 1 or more sites with 4 mm or greater CAL; 3.1 (95% CI, 1.5–6.4) for having 1 or more sites with 5 mm or greater CAL; and 2.2 (95% CI, 1.2–3.9) for having incident attachment loss (in comparison with those who had never smoked cannabis). Tobacco smoking was strongly associated with periodontal disease experience, but there was no interaction between cannabis use and tobacco smoking in predicting the condition’s occurrence.
Conclusion
Cannabis smoking may be a risk factor for periodontal disease that is independent of the use of tobacco.
doi:10.1001/jama.299.5.525
PMCID: PMC2823391  PMID: 18252882
22.  Comparison of Clinical Trial Recruitment Populations: Treatment-Seeking Characteristics of Opioid-, Cocaine-, and Cannabis-Using Participants 
This study examined the treatment history and intention to seek treatment among 489 individuals interested in substance use disorder clinical trial participation. Opioid and cocaine users were more likely than cannabis users to report having received treatment for substance use in the past, and more likely than cannabis users to report planning to seek treatment for substance use before exposure to recruitment advertising. Free cost was the aspect of clinical trial participation that most influenced the decision to make an intake evaluation appointment for opioid-dependent patients as compared to cocaine and cannabis-dependent participants, and the availability of individual psychotherapy most influenced those who were cannabis-dependent. Cannabis-dependent individuals evaluated for clinical trial participation reported that recruitment advertising was an important factor in leading them to seek treatment. These results have implications for clinical trial recruitment as well as public health efforts directed at encouraging cannabis-dependent individuals to seek treatment.
doi:10.1016/j.jsat.2011.01.005
PMCID: PMC3082005  PMID: 21439756
Opioids; cannabis; cocaine; recruitment
23.  Aerobic Exercise Training Reduces Cannabis Craving and Use in Non-Treatment Seeking Cannabis-Dependent Adults 
PLoS ONE  2011;6(3):e17465.
Background
Cannabis dependence is a significant public health problem. Because there are no approved medications for this condition, treatment must rely on behavioral approaches empirically complemented by such lifestyle change as exercise.
Aims
To examine the effects of moderate aerobic exercise on cannabis craving and use in cannabis dependent adults under normal living conditions.
Design
Participants attended 10 supervised 30-min treadmill exercise sessions standardized using heart rate (HR) monitoring (60–70% HR reserve) over 2 weeks. Exercise sessions were conducted by exercise physiologists under medical oversight.
Participants
Sedentary or minimally active non-treatment seeking cannabis-dependent adults (n = 12, age 25±3 years, 8 females) met criteria for primary cannabis dependence using the Substance Abuse module of the Structured Clinical Interview for DSM-IV (SCID).
Measurements
Self-reported drug use was assessed for 1-week before, during, and 2-weeks after the study. Participants viewed visual cannabis cues before and after exercise in conjunction with assessment of subjective cannabis craving using the Marijuana Craving Questionnaire (MCQ-SF).
Findings
Daily cannabis use within the run-in period was 5.9 joints per day (SD = 3.1, range 1.8–10.9). Average cannabis use levels within the exercise (2.8 joints, SD = 1.6, range 0.9–5.4) and follow-up (4.1 joints, SD = 2.5, range 1.1–9.5) periods were lower than during the run-in period (both P<.005). Average MCQ factor scores for the pre- and post-exercise craving assessments were reduced for compulsivity (P  = .006), emotionality (P  = .002), expectancy (P  = .002), and purposefulness (P  = .002).
Conclusions
The findings of this pilot study warrant larger, adequately powered controlled trials to test the efficacy of prescribed moderate aerobic exercise as a component of cannabis dependence treatment. The neurobiological mechanisms that account for these beneficial effects on cannabis use may lead to understanding of the physical and emotional underpinnings of cannabis dependence and recovery from this disorder.
Trial Registration
ClinicalTrials.gov NCT00838448]
doi:10.1371/journal.pone.0017465
PMCID: PMC3050879  PMID: 21408154
24.  Actions of delta-9-tetrahydrocannabinol in cannabis 
Cannabis use disorders have been recently identified as a relevant clinical issue: a subset of cannabis smokers seeks treatment for their cannabis use, yet few succeed in maintaining long-term abstinence. The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis, delta-9-tetrahydrocannabinol (THC) are mediated by the cannabinoid CB1 receptor. The CB1 receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration, a phenomenon verified across species. This paper will review findings implicating the CB1 receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement, factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences. Opioidergic modulation of these effects is also discussed.
doi:10.1080/09540260902782752
PMCID: PMC2731700  PMID: 19367504
25.  Double-Blind Fluoxetine Trial in Comorbid MDD-CUD Youth and Young Adults 
Drug and alcohol dependence  2010;112(1-2):39-45.
Objective
This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD.
Methods
We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study.
Results
Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups.
Conclusions
Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.
doi:10.1016/j.drugalcdep.2010.05.010
PMCID: PMC2946416  PMID: 20576364
Cannabis Use Disorder; Major Depressive Disorder; Fluoxetine; Cognitive Behavioral Therapy; Motivation Enhancement Therapy

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