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1.  Reaching out towards cannabis: approach-bias in heavy cannabis users predicts changes in cannabis use 
Addiction (Abingdon, England)  2011;106(9):1667-1674.
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.
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.
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.
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.
PMCID: PMC3178782  PMID: 21518067
Approach avoidance task; approach-bias; cannabis; cannabis use disorder; craving; dependence
2.  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.
PMCID: PMC3689035  PMID: 23801968
cannabis; implicit association test; cannabis use disorder; craving; affective associations
3.  Can reduce - the effects of chat-counseling and web-based self-help, web-based self-help alone and a waiting list control program on cannabis use in problematic cannabis users: a randomized controlled trial 
BMC Psychiatry  2013;13:305.
In European countries, including Switzerland, as well as in many states worldwide, cannabis is the most widely used psychoactive substance after alcohol and tobacco. Although approximately one in ten users develop serious problems of dependency, only a minority attends outpatient addiction counseling centers. The offer of a combined web-based self-help and chat counseling treatment could potentially also reach those users who hesitate to approach such treatment centers and help them to reduce their cannabis use.
This paper presents the protocol for a three-armed randomized controlled trial that will test the effectiveness of a web-based self-help intervention in combination with, or independent of, tailored chat counseling compared to a waiting list in reducing or enabling the abstention from cannabis use in problematic users. The primary outcome will be the weekly quantity of cannabis used. Secondary outcome measures will include the number of days per week on which cannabis is used, the severity of cannabis use disorder, the severity of cannabis dependence, cannabis withdrawal symptoms, cannabis craving, the use of alcohol, tobacco, and other non-cannabis illicit drugs, changes in mental health symptoms, and treatment retention. The self-help intervention will consist of 8 modules designed to reduce cannabis use based on the principles of motivational interviewing, self-control practices, and methods of cognitive behavioral therapy. The two additional individual chat-counseling sessions in the additional chat condition will be based on the same therapy approaches and tailored to participants’ self-help information data and personal problems. The predictive validity of participants’ baseline characteristics on treatment retention and outcomes will be explored.
To the best of our knowledge, this will be the first randomized controlled trial to test the effectiveness of online self-help therapy in combination or without chat counseling in reducing or enabling the abstention from cannabis use. It will also investigate predictors of outcome and retention for these interventions. This trial is registered at Current Controlled Trials and is traceable as ISRCTN59948178.
PMCID: PMC3830542  PMID: 24228630
Cannabis; Internet; Chat; Web-based; Self-help; Cognitive behavioral therapy; Motivational interviewing
4.  Anxiety Sensitivity and Marijuana Use: An Analysis from Ecological Momentary Assessment 
Depression and anxiety  2011;28(5):420-426.
The cognitive factor of Anxiety Sensitivity (AS; the fear of anxiety and related bodily sensations), is theorized to play a role in cannabis use and its disorders. Lower-order facets of AS (physical concerns, mental incapacitation concerns, social concerns) may be differentially related to cannabis use behavior. However, little is known about the impact of AS facets on the immediate antecedents of cannabis use.
The present study used ecological momentary assessment (EMA) to prospectively examine the relations between specific facets of AS, cannabis craving, state anxiety, and cannabis use in the natural environment using real-world data about ad-lib cannabis use episodes. Participants were 49 current cannabis users (38.8% female).
AS-mental incapacitation fears were related to significantly greater severity of cannabis-related problems at baseline. During the EMA period, AS-mental incapacitation and AS-social concerns significantly interacted with cannabis craving to prospectively predict subsequent cannabis use. Specifically, individuals with higher craving and either higher AS-mental incapacitation or AS-social concerns were the most likely to subsequently use cannabis. In contrast to prediction, no AS facet significantly moderated the relationship between state anxiety and cannabis use.
These findings suggest facets of AS (mental incapacitation and social fears) interact with cannabis craving to predict cannabis use. Findings also suggest differential relations between facets of anxiety sensitivity and cannabis-related behaviors.
PMCID: PMC3086947  PMID: 21449005
anxiety sensitivity; anxiety; marijuana; cannabis; ecological momentary assessment
5.  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.
PMCID: PMC3021959  PMID: 19081202
Simultaneous use; cannabis; tobacco; abuse; dependence; twin
6.  Approach to cannabis use disorder in primary care 
Canadian Family Physician  2014;60(9):801-808.
To review the clinical features and complications of at-risk cannabis use and cannabis use disorder, and to outline an office-based protocol for screening, identifying, and managing this disorder.
Sources of information
PubMed was searched for controlled trials, observational studies, and reviews on cannabis use among adolescents and young adults; cannabis-related medical and psychiatric harms; cannabis use disorder and its treatment; and lower-risk cannabis use guidelines.
Main message
Physicians should ask all patients about cannabis use. They should ask adolescents and young adults and those at highest risk of cannabis-related harms (those with concurrent psychiatric or substance use disorders) more frequently. Physicians should also ask about cannabis use in patients who have problems that could be caused by cannabis, such as mood disorders, psychosis, and respiratory symptoms. In patients who report cannabis use, physicians should inquire about frequency and amount, tolerance and withdrawal symptoms, attempts to reduce use, and cannabis-related harms. Lower-risk cannabis users smoke, inhale, or ingest cannabis occasionally without evidence of school, work, or social dysfunction; those with problematic use often use cannabis daily or almost daily, have difficulty reducing their use, and have impaired school, work, or social functioning. Physicians should offer all patients with problematic use brief advice and counseling, focusing on the health effects of cannabis and setting a goal of abstinence (some higher-risk groups should not use cannabis at all) or reduced use, and they should provide practical strategies to reduce cannabis use. Physicians should incorporate simple motivational interviewing techniques into the counseling sessions. They should refer those patients who are unable to reduce use or who are experiencing harms from cannabis use to specialized care, while ensuring those patients remain connected to primary care. As well, physicians should give information on lower-risk cannabis use to all cannabis users.
Physicians should screen all patients in their practices at least once for cannabis use, especially those who have problems that might be caused by cannabis. Physicians should screen those at higher risk more often, at least annually. Lower-risk cannabis use should be distinguished from problematic use. Brief counseling should be provided to those with problematic use; these patients should be referred to specialists if they are unable to reduce or cease use.
PMCID: PMC4162694  PMID: 25217674
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.
PMCID: PMC3442352  PMID: 22669173
marijuana; genetics; endocannabinoid; hippocampus; amygdala; addiction & substance abuse; amygdala; endocannabinoid; genetics; hippocampus; imaging; clinical or preclinical; marijuana; neuroanatomy; neurogenetics
8.  Aerobic Exercise Training Reduces Cannabis Craving and Use in Non-Treatment Seeking Cannabis-Dependent Adults 
PLoS ONE  2011;6(3):e17465.
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.
To examine the effects of moderate aerobic exercise on cannabis craving and use in cannabis dependent adults under normal living conditions.
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.
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).
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).
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).
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 NCT00838448]
PMCID: PMC3050879  PMID: 21408154
9.  Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users 
NeuroImage  2009;49(1):1133-1143.
Despite an increased understanding of the pharmacology and long-term cognitive effects of cannabis in humans, there has been no research to date examining its chronic effects upon reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The reward deficiency syndrome (RDS) of addiction posits that there are deficits in dopamine (DA) motivational circuitry for non-drug rewards, such that only drugs of abuse are capable of normalizing DA in the ventral striatum (VS). Alternatively, the opponent process theory (OPT) holds that in individuals prone to drug use, there exists some form of mesolimbic hyperactivity, in which there is a bias towards reward-centred behaviour concomitant with impulsivity. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naïve controls during a monetary incentive delay (MID) task. Despite no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. We also observed a number of group differences following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards.
PMCID: PMC2764826  PMID: 19631753
10.  Sensory Gating Impairments in Heavy Cannabis Users are Associated with Altered Neural Oscillations 
Behavioral neuroscience  2009;123(4):894-904.
Central cannabinoid receptors are thought to mediate neural oscillations and are localized to brain regions implicated in auditory P50 sensory gating, including the hippocampus and neocortex. The current study therefore examined if neural oscillations evoked by the paired clicks (S1, S2) are associated with impaired P50 gating reported in cannabis users. Seventeen heavy cannabis users and 16 cannabis naïve controls participated. Analyses included P50 amplitudes, and time x frequency analyses examining event-related spectral perturbations (ERSP) and inter-trial coherence (ITC). In agreement with prior studies, cannabis users exhibited reduced P50 gating. The ERSP analysis yielded attenuated high frequency activity in the beta range (13-29 Hz) post-S1 and in the gamma range (30-50 Hz) post-S2 in the cannabis group, compared to the control group. Attenuated ITC was also observed in the cannabis group in the post-S2 theta band (4-7 Hz). Greater levels of cannabis use were positively associated with high P50 ratios and negatively with post-S2 ERSP gamma power. These findings suggest that heavy cannabis use is associated with aberrant beta and gamma activity in the dual-click procedure, which corroborates recent work demonstrating disruption of beta/gamma by cannabinoid receptor (CB1) agonists in a rat analogue of this procedure and highlights the translational potential of the dual-click procedure.
PMCID: PMC3536882  PMID: 19634950
P50; Marijuana; auditory gating; beta; gamma; time-frequency
11.  An fMRI Study of Neuronal Activation in Schizophrenia Patients with and without Previous Cannabis Use 
Previous studies have mostly shown positive effects of cannabis use on cognition in patients with schizophrenia, which could reflect lower neurocognitive vulnerability. There are however no studies comparing whether such cognitive differences have neuronal correlates. Thus, the aim of the present study was to compare whether patients with previous cannabis use differ in brain activation from patients who has never used cannabis. The patients groups were compared on the ability to up-regulate an effort mode network during a cognitive task and down-regulate activation in the same network during a task-absent condition. Task-present and task-absent brain activation was measured by functional magnetic resonance neuroimaging (fMRI). Twenty-six patients with a DSM-IV and ICD-10 diagnosis of schizophrenia were grouped into a previous cannabis user group and a no-cannabis group. An auditory dichotic listening task with instructions of attention focus on either the right or left ear stimulus was used to tap verbal processing, attention, and cognitive control, calculated as an aggregate score. When comparing the two groups, there were remaining activations in the task-present condition for the cannabis group, not seen in the no-cannabis group, while there was remaining activation in the task-absent condition for the no-cannabis group, not seen in the cannabis group. Thus, the patients with previous cannabis use showed increased activation in an effort mode network and decreased activation in the default mode network as compared to the no-cannabis group. It is concluded that the present study show some differences in brain activation to a cognitively challenging task between previous cannabis and no-cannabis schizophrenia patients.
PMCID: PMC3483569  PMID: 23115554
schizophrenia; fMRI; cannabis; dichotic listening; default mode network; effort mode network; brain activation; cognitive control
12.  Effectiveness of a Self-Guided Web-Based Cannabis Treatment Program: Randomized Controlled Trial 
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.
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.
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).
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.
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.
PMCID: PMC3636012  PMID: 23470329
marijuana; Internet intervention; computer-assisted therapy; addiction; randomized controlled trial
13.  Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: Preliminary results 
Psychiatry research  2013;214(2):122-131.
Craving is a major motivator underlying drug use and relapse but the neural correlates of cannabis craving are not well understood. This study sought to determine whether visual cannabis cues increase cannabis craving and whether cue-induced craving is associated with regional brain activation in cannabis-dependent individuals. Cannabis craving was assessed in 16 cannabis-dependent adult volunteers while they viewed cannabis cues during a functional MRI (fMRI) scan. The Marijuana Craving Questionnaire was administered immediately before and after each of three cannabis cue-exposure fMRI runs. FMRI blood-oxygenation-level-dependent (BOLD) signal intensity was determined in regions activated by cannabis cues to examine the relationship of regional brain activation to cannabis craving. Craving scores increased significantly following exposure to visual cannabis cues. Visual cues activated multiple brain regions, including inferior orbital frontal cortex, posterior cingulate gyrus, parahippocampal gyrus, hippocampus, amygdala, superior temporal pole, and occipital cortex. Craving scores at baseline and at the end of all three runs were significantly correlated with brain activation during the first fMRI run only, in the limbic system (including amygdala and hippocampus) and paralimbic system (superior temporal pole), and visual regions (occipital cortex). Cannabis cues increased craving in cannabis-dependent individuals and this increase was associated with activation in the limbic, paralimbic, and visual systems during the first fMRI run, but not subsequent fMRI runs. These results suggest that these regions may mediate visually cued aspects of drug craving. This study provides preliminary evidence for the neural basis of cue-induced cannabis craving and suggests possible neural targets for interventions targeted at treating cannabis dependence.
PMCID: PMC3904759  PMID: 24035535
drug abuse; functional MRI; addiction
14.  "CAN Stop" - Implementation and evaluation of a secondary group prevention for adolescent and young adult cannabis users in various contexts - study protocol 
Current research shows that overall numbers for cannabis use among adolescents and young adults dropped in recent years. However, this trend is much less pronounced in continuous cannabis use. With regard to the heightened risk for detrimental health- and development-related outcomes, adolescents and young adults with continuous cannabis use need special attention. The health services structure for adolescents and young adults with substance related problems in Germany, is multifaceted, because different communal, medical and judicial agencies are involved. This results in a rather decentralized organizational structure of the help system. This and further system-inherent characteristics make the threshold for young cannabis users rather high. Because of this, there is a need to establish evidence-based low-threshold help options for young cannabis users, which can be easily disseminated. Therefore, a training programme for young cannabis users (age 14-21) was developed in the "CAN Stop" project. Within the project, we seek to implement and evaluate the training programme within different institutions of the help system. The evaluation is sensitive to the different help systems and their specific prerequisites. Moreover, within this study, we also test the practicability of a training provision through laypersons.
The CAN Stop study is a four-armed randomized wait-list controlled trial. The four arms are needed for the different help system settings, in which the CAN Stop training programme is evaluated: (a) the drug addiction aid and youth welfare system, (b) the out-patient medical system, (c) the in-patient medical system and (d) prisons for juvenile offenders. Data are collected at three points, before and after the training or a treatment as usual, and six months after the end of either intervention.
The CAN Stop study is expected to provide an evidence-based programme for young cannabis users seeking to reduce or quit their cannabis use. Moreover, we seek to gain knowledge about the programme's utility within different settings of the German help system for young cannabis users and information about the settings' specific clientele. The study protocol is discussed with regard to potential difficulties within the different settings.
Trial registration
PMCID: PMC3090321  PMID: 21501479
15.  Does Cannabis Use Predict Poor Outcome for Heroin-Dependent Patients on Maintenance Treatment? A Review of Past Findings, and More Evidence Against 
Addiction (Abingdon, England)  2003;98(3):269-279.
To determine whether cannabinoid-positive urine specimens in heroin-dependent outpatients predict other drug use or impairments in psychosocial functioning, and whether such outcomes are better predicted by cannabis-use disorders than by cannabis use itself.
Retrospective analyses of three clinical trials; each included a behavioral intervention (contingency management) for cocaine or heroin use during methadone maintenance. Trials lasted 25–29 weeks; follow-up evaluations occurred 3, 6, and 12 months posttreatment. For the present analyses, data were pooled across trials where appropriate.
Urban outpatient methadone clinic.
408 polydrug abusers meeting methadone-maintenance criteria.
Participants were categorized as nonusers, occasional users, or frequent users of cannabis based on thrice-weekly qualitative urinalyses. Cannabis-use disorders were assessed with the Diagnostic Interview Schedule III-R. Outcome measures included proportion of cocaine- and opiate-positive urines and the Addiction Severity Index (at intake and follow-ups).
Cannabis use was not associated with retention, use of cocaine or heroin, or any other outcome measure during or after treatment. Our analyses had a power of .95 to detect an r2 of .11 between cannabis use and heroin or cocaine use; the r2 we detected was less than .03 and nonsignificant. A previous finding that cannabis use predicted lapse to heroin use in heroin-abstinent patients did not replicate in our sample. However, cannabis-use disorders were weakly associated with psychosocial problems at posttreatment follow-up.
Cannabinoid-positive urines need not be a major focus of clinical attention during treatment for opiate dependence, unless patients report symptoms of cannabis-use disorders.
PMCID: PMC2943839  PMID: 12603227
cannabis; methadone maintenance; treatment outcome
16.  Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users 
Drug abuse and other psychiatric conditions (e.g., schizophrenia) have been associated with a diminished neural response to errors, particularly in the anterior cingulate cortex (ACC) thought critical to error processing. A diminished capacity for detecting errors has been linked to clinical symptoms including the loss of insight, delusions and perseverative behaviour. Sixteen active chronic cannabis users and 16 control participants were administered a Go/No-go response inhibition task during event-related fMRI data collection. The task provides measures of inhibitory control and error awareness. Cannabis users’ inhibitory control performance was equivalent to that of the control group, but the former demonstrated a significant deficit in awareness of commission errors. Cannabis users demonstrated a diminished capacity for monitoring their behaviour that was associated with hypoactivity in the ACC and right insula. In addition, increased levels of hypoactivity in both the ACC and right insula regions were significantly correlated with error awareness rates in the cannabis group (but not controls). These difficulties are consistent with previous reports of hypoactivity in the neural systems underlying cognitive control and the monitoring of interoceptive awareness in chronic drug users, and highlight the potential relationship between cognitive dysfunction and behavioural deficits that have the potential to contribute to the maintenance of drug abuse.
PMCID: PMC2743772  PMID: 19553917
Performance monitoring; error-related; drug addiction; marijuana; insula; cognitive control
17.  Do reward-processing deficits in schizophrenia-spectrum disorders promote cannabis use? An investigation of physiological response to natural rewards and drug cues 
Dysfunctional reward processing is present in individuals with schizophrenia-spectrum disorders (SSD) and may confer vulnerability to addiction. Our objective was to identify a deficit in patients with SSD on response to rewarding stimuli and determine whether this deficit predicts cannabis use.
We divided a group of patients with SSD and nonpsychotic controls into cannabis users and nonusers. Response to emotional and cannabis-associated visual stimuli was assessed using self-report, event-related potentials (using the late positive potential [LPP]), facial electromyography and skin-conductance response.
Our sample comprised 35 patients with SSD and 35 nonpsychotic controls. Compared with controls, the patients with SSD showed blunted LPP response to pleasant stimuli (p = 0.003). Across measures, cannabis-using controls showed greater response to pleasant stimuli than to cannabis stimuli whereas cannabis-using patients showed little bias toward pleasant stimuli. Reduced LPP response to pleasant stimuli was predictive of more frequent subsequent cannabis use (β = −0.24, p = 0.034).
It is not clear if the deficit associated with cannabis use is specific to rewarding stimuli or nonspecific to any kind of emotionally salient stimuli.
The LPP captures a reward-processing deficit in patients with SSD and shows potential as a biomarker for identifying patients at risk of heavy cannabis use.
PMCID: PMC4160363  PMID: 24913137
18.  Cannabis use and mental health in young people: cohort study 
BMJ : British Medical Journal  2002;325(7374):1195-1198.
To determine whether cannabis use in adolescence predisposes to higher rates of depression and anxiety in young adulthood.
Seven wave cohort study over six years.
44 schools in the Australian state of Victoria.
A statewide secondary school sample of 1601 students aged 14-15 followed for seven years.
Main outcome measure
Interview measure of depression and anxiety (revised clinical interview schedule) at wave 7.
Some 60% of participants had used cannabis by the age of 20; 7% were daily users at that point. Daily use in young women was associated with an over fivefold increase in the odds of reporting a state of depression and anxiety after adjustment for intercurrent use of other substances (odds ratio 5.6, 95% confidence interval 2.6 to 12). Weekly or more frequent cannabis use in teenagers predicted an approximately twofold increase in risk for later depression and anxiety (1.9, 1.1 to 3.3) after adjustment for potential baseline confounders. In contrast, depression and anxiety in teenagers predicted neither later weekly nor daily cannabis use.
Frequent cannabis use in teenage girls predicts later depression and anxiety, with daily users carrying the highest risk. Given recent increasing levels of cannabis use, measures to reduce frequent and heavy recreational use seem warranted.
What is already known on this topicFrequent recreational use of cannabis has been linked to high rates of depression and anxiety in cross sectional surveys and studies of long term usersWhy cannabis users have higher rates of depression and anxiety is uncertainPrevious longitudinal studies of cannabis use in youth have not analysed associations with frequent cannabis useWhat this study addsA strong association between daily use of cannabis and depression and anxiety in young women persists after adjustment for intercurrent use of other substancesFrequent cannabis use in teenage girls predicts later higher rates of depression and anxietyDepression and anxiety in teenagers do not predict later cannabis use; self medication is therefore unlikely to be the reason for the association
PMCID: PMC135489  PMID: 12446533
19.  Intermittent Marijuana Use Is Associated with Improved Retention in Naltrexone Treatment for Opiate-Dependence 
Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six-month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean = 112.8, SE = 17.5), compared to abstinent (median = 35; mean = 47.3, SE = 9.2) or consistent users (median = 35; mean = 68.3, SE = 14.1) (log rank = 12.2, df = 2, p = .002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism.
PMCID: PMC2753886  PMID: 19444734
20.  Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter fMRI study 
Early-onset cannabis use has been associated with later (ab)use, mental health problems (psychosis, depression) and abnormal development of cognition and brain function. During adolescence ongoing neurodevelopmental maturation and experience shape the neural circuitry underlying complex cognitive functions such as memory and executive control. Prefrontal and temporal regions are critically involved in these functions. Maturational processes leave these brain areas prone to the potentially harmful effects of cannabis use.
We performed a two-site (US and NL; pooled data) functional MRI study with a cross-sectional design, investigating the effects of adolescent cannabis use on working memory (WM) and associative memory (AM) brain function in twenty-one abstinent but frequent cannabis using boys (age 13 – 19) and compared them with twenty-four non-using peers. Brain activity during WM was assessed before and following rule-based learning (automatization). AM was assessed using a pictorial hippocampal-dependent memory task.
Cannabis users performed normally on both memory tasks. During WM assessment cannabis users showed excessive activity in prefrontal regions when a task was novel, whereas automatization of the task reduced activity to the same level in users and controls. No effect of cannabis use on AM-related brain function was found.
In adolescent cannabis users the WM system was overactive during a novel task, suggesting functional compensation. Inefficient WM recruitment was not related to a failure in automatization, but became evident when processing continuously changing information. The results seem to confirm the vulnerability of still developing frontal lobe functioning for early-onset cannabis use.
PMCID: PMC2918244  PMID: 20494266
cannabis; adolescence; early-onset; fMRI; memory
21.  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).
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.
PMCID: PMC3458862  PMID: 23049760
22.  Effectiveness of Different Web-Based Interventions to Prepare Co-Smokers of Cigarettes and Cannabis for Double Cessation: A Three-Arm Randomized Controlled Trial 
The relationship between tobacco and cannabis use is strong. When co-smokers try to quit only one substance, this relationship often leads to a substitution effect, that is, the increased use of the remaining substance. Stopping the use of both substances simultaneously is therefore a reasonable strategy, but co-smokers rarely report feeling ready for simultaneous cessation. Thus, the question of how co-smokers can be motivated to attempt a simultaneous cessation has arisen. To reach as many co-smokers as possible, we developed brief Web-based interventions aimed at enhancing the readiness to simultaneously quit tobacco and cannabis use.
Our aim was to analyze the efficacy of three different Web-based interventions designed to enhance co-smokers’ readiness to stop tobacco and cannabis use simultaneously.
Within a randomized trial, three brief Web-based and fully automated interventions were compared. The first intervention combined the assessment of cigarette dependence and problematic cannabis use with personalized, normative feedback. The second intervention was based on principles of motivational interviewing. As an active psychoeducational control group, the third intervention merely provided information on tobacco, cannabis, and the co-use of the two substances. The readiness to quit tobacco and cannabis simultaneously was measured before and after the intervention (both online) and 8 weeks later (online or over the phone). Secondary outcomes included the frequency of cigarette and cannabis use, as measured at baseline and after 8 weeks.
A total of 2467 website users were assessed for eligibility based on their self-reported tobacco and cannabis co-use, and 325 participants were ultimately randomized and analyzed. For the post-intervention assessment, generalized estimating equations revealed a significant increase in the readiness to quit tobacco and cannabis in the total sample (B=.33, 95% CI 0.10-0.56, P=.006). However, this effect was not significant for the comparison between baseline and the 8-week follow-up assessment (P=.69). Furthermore, no differential effects between the interventions were found, nor were any significant intervention or time effects found on the frequency of tobacco or cannabis use.
In the new field of dual interventions for co-smokers of tobacco and cannabis, Web-based interventions can increase the short-term readiness to quit tobacco and cannabis simultaneously. The studied personalized techniques were no more effective than was psychoeducation. The analyzed brief interventions did not change the secondary outcomes, that is the frequency of tobacco and cannabis use.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 56326375; (Archived by WebCite at
PMCID: PMC4275498  PMID: 25486674
tobacco; cannabis; co-smoking; simultaneous cessation; motivational enhancement; personalized feedback; web-based intervention; motivational interviewing
23.  The Effect of Chronic Cannabinoids on Broadband EEG Neural Oscillations in Humans 
Neuropsychopharmacology  2012;37(10):2184-2193.
Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10–50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis.
PMCID: PMC3422484  PMID: 22713908
cannabis; cannabinoid; neural oscillations; neural synchrony; EEG; auditory steady-state response; cannabinoids; addiction & substance abuse; biological psychiatry; psychopharmacology; cannabis; neural oscillations; neural synchrony; EEG; auditory steady-state response
24.  Social Anxiety and Cannabis Use: An Analysis from Ecological Momentary Assessment 
Journal of Anxiety Disorders  2011;26(2):297-304.
Individuals with elevated social anxiety appear especially vulnerable to cannabis-related problems, yet little is known about the antecedents of cannabis-related behaviors among this high-risk population. The present study used ecological momentary assessment (EMA) to examine the relations among social anxiety, cannabis craving, state anxiety, situational variables, and cannabis use in the natural environment during ad-lib cannabis use episodes. Participants were 49 current cannabis users. During the two-week EMA period, social anxiety significantly interacted with cannabis craving to predict cannabis use both cross-sectionally and prospectively. Specifically, individuals with higher social anxiety and craving were most likely to use cannabis. There was a significant social anxiety X state anxiety X others’ use interaction such that when others were using cannabis, those with elevations in both trait social anxiety and state anxiety were the most likely to use cannabis.
PMCID: PMC3268873  PMID: 22246109
social anxiety; state anxiety; cannabis; marijuana; craving; ecological momentary assessment
25.  Motives for cannabis use in high-risk adolescent users 
The present investigation examined the relationships between motives for cannabis use and negative consequences associated with cannabis use following a brief intervention. The sample consisted of 205 adolescent cannabis users (66.3% male), who were recruited in high schools and randomly assigned to a brief two-session motivational enhancement therapy (MET) or an educational feedback control (EFC). Results supported the hypothesis that using cannabis to cope with negative affect would predict the number of problems and dependence symptoms related to cannabis use, after controlling for age, gender, years and frequency of cannabis use, and internalizing and externalizing behavior problems. Significant interactions between internalizing behavior problems and the coping motive showed that using to cope was associated with a higher number of cannabis dependence symptoms among adolescents reporting lower levels internalizing behavior problems. Findings support the potential utility of conducting further research to explore the coping motive as an important indicator of problematic cannabis use.
PMCID: PMC3211084  PMID: 21688873
cannabis; marijuana; adolescents; cannabis use motives; internalizing behavior problems

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