Dan I. Lubman

Regional brain abnormalities associated with long-term heavy cannabis use.

CONTEXT Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain. OBJECTIVE To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala. DESIGN Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. SETTING Participants were recruited from the general community and underwent imaging at a hospital research facility. PARTICIPANTS Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years). MAIN OUTCOME MEASURES Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. RESULTS Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group. CONCLUSIONS These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

Parenting Factors Associated with Reduced Adolescent Alcohol Use: A Systematic Review of Longitudinal Studies:

Objective: To identify parenting strategies associated with adolescent alcohol consumption that parents can use to implement new national guidelines regarding alcohol consumption by people under the age of 18. Methods: A systematic search of academic literature employing the PRISMA method identified 77 relevant articles. Inclusion criteria for the review were (i) longitudinal cohort studies; (ii) measurement of one or more parenting factors during adolescence or pre-adolescence (between the ages of 8 and 17) as a predictor (iii) outcome measurement of any alcohol use and/or alcohol related problems during adolescence at least one time point after the initial parenting factor was measured, and/or problem drinking in adulthood. Studies were excluded if alcohol use was combined with other substance use or problem behaviour as an outcome variable, or if different parenting factors were combined as a single predictor variable for analysis. Stouffers method of combining p values was used to determine whether associations between variables were reliable. Results: Twelve parenting variables were investigated in these studies: parental modelling, provision of alcohol, alcohol-specific communication, disapproval of adolescent drinking, general discipline, rules about alcohol, parental monitoring, parent–child relationship quality, family conflict, parental support, parental involvement, and general communication. We found that delayed alcohol initiation was predicted by: parental modelling, limiting availability of alcohol to the child, parental monitoring, parent–child relationship quality, parental involvement and general communication. Reduced levels of later drinking by adolescents were predicted by: parental modelling, limiting availability of alcohol to the child, disapproval of adolescent drinking, general discipline, parental monitoring, parent–child relationship quality, parental support and general communication. Conclusions: A number of parenting strategies were identified that parents can use to reduce their adolescents alcohol consumption. These could be promoted to parents to help them implement new national guidelines on alcohol use.

The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis.

Objective:  Studies investigating the impact of comorbid substance use disorders (SUD) in psychosis have tended to focus on cross‐sectional data, with few studies examining the effects of substance use course on clinical outcome. The main aim of the present study was to assess the impact of baseline SUD and course of SUD on remission of positive symptoms.

Attentional bias for drug cues in opiate dependence

BACKGROUND In a number of theories of compulsive drug use conditioned responses to stimuli associated with drug taking play a pivotal role. For example, according to incentive-sensitization theory (Robinson & Berridge, 1993), drug-related stimuli selectively capture attention, and the neural mechanisms underlying this attentional bias play a key role in the development and maintenance of drug dependence, and in relapse. However, there has been little work that assesses attentional biases in addiction. METHODS We used a pictorial probe detection task to investigate whether there is an attentional bias to stimuli associated with drug use in opiate dependence. Stimuli presented included pairs of drug-related and matched neutral pictures. Methadone-maintained opiate addicts (N = 16) were compared with age-matched controls (N = 16). RESULTS A mixed design analysis of variance of response times to probes revealed a significant three-way interaction of group x drug picture location x probe location. Opiate addicts had relatively faster reaction times to probes that replaced drug pictures rather than neutral pictures, consistent with the predicted attentional bias to drug-related stimuli. CONCLUSIONS These results support the idea that an attentional bias for drug-related stimuli occurs in opiate dependence. This is consistent with the concept of a central role for such salient stimuli in compulsive drug use.

Effect of long-term cannabis use on axonal fibre connectivity

Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The aim of this study was to examine axonal fibre pathways across the brain for evidence of microstructural alterations associated with long-term cannabis use and to test whether age of regular cannabis use is associated with severity of any microstructural change. To this end, diffusion-weighted magnetic resonance imaging and brain connectivity mapping techniques were performed in 59 cannabis users with longstanding histories of heavy use and 33 matched controls. Axonal connectivity was found to be impaired in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum and commissural fibres. Radial and axial diffusivity in these pathways were associated with the age at which regular cannabis use commenced. Our findings indicate long-term cannabis use is hazardous to the white matter of the developing brain. Delaying the age at which regular use begins may minimize the severity of microstructural impairment.

The neurobiological basis of temperament: Towards a better understanding of psychopathology

The ability to characterise psychopathologies on the basis of their underlying neurobiology is critical in improving our understanding of disorder etiology and making more effective diagnostic and treatment decisions. Given the well-documented relationship between temperament (i.e. core personality traits) and psychopathology, research investigating the neurobiological substrates that underlie temperament is potentially key to our understanding of the biological basis of mental disorder. We present evidence that specific areas of the prefrontal cortex (including the dorsolateral prefrontal, anterior cingulate, and orbitofrontal cortices) and limbic structures (including the amygdala, hippocampus and nucleus accumbens) are key regions associated with three fundamental dimensions of temperament: Negative Affect, Positive Affect, and Constraint. Proposed relationships are based on two types of research: (a) research into the neurobiological correlates of affective and cognitive processes underlying these dimensions; and (b) research into the neurobiology of various psychopathologies, which have been correlated with these dimensions. A model is proposed detailing how these structures might comprise neural networks whose functioning underlies the three temperaments. Recommendations are made for future research into the neurobiology of temperament, including the need to focus on neural networks rather than individual structures, and the importance of prospective, longitudinal, multi-modal imaging studies in at-risk youth.

The role of affective dysregulation in drug addiction.

Although affective and substance use disorders frequently co-occur, the role of affective dysregulation in addiction is often overlooked. This paper reviews the role of affective dysregulation in the initiation and maintenance of substance use disorders (SUDs), presenting evidence for a relationship between SUD and three biologically-based dimensions of affective temperament and behaviour: negative affect (NA), positive affect (PA), and effortful control (EC). High NA, low EC, and both high and low PA were each found to play a role in conferring risk and maintaining substance use behaviours, although the strength of their influence differed depending on stage of illness (i.e., early onset use through to addiction). Given these findings, we argue that future research should explicitly consider how changes within affective systems may underlie the development of SUDs. A better understanding of the role of affective dysregulation in addiction will aid in clarifying how risk is conferred, as well as how addictive behaviours are maintained, thereby informing the development of preventative strategies and novel treatments. Future studies should continue to examine the role of high NA in SUDs, and further examine the respective roles of high PA, low PA, and low EC, as well as identifying the affective characteristics that predispose high-risk individuals to later substance use problems.

Inhalant abuse among adolescents: neurobiological considerations.

Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABAA, glycine and 5HT3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long‐term alterations in the function of NMDA and GABAA receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development.

Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT1A receptors in ventral prefrontal cortex in schizophrenia

We previously reported increased glutamatergic innervation in orbital frontal cortex in schizophrenia. In view of the evidence that one serotonin (5-HT) receptor, the 5-HT(1A) subtype, is associated with cortical glutamatergic neurons, we have used quantitative receptor autoradiography to measure the specific binding of the 5-HT(1A) receptor ligand [3H]8-OH-DPAT (2 nM) in sections of orbital frontal cortex taken from 18 control and 12 schizophrenic postmortem brains. Schizophrenic patients, as compared with controls, had increased 5-HT(1A) receptor binding in the three orbital frontal regions examined. These effects were pronounced in the male subgroup, and were most apparent in the outer cortical laminae. These data are consistent with the hypothesis that schizophrenia is associated with an abnormal glutamatergic afferent innervation of orbital frontal cortex.

Understanding Drug Addiction: A Neuropsychological Perspective

The purpose of the present review is to describe the neuropsychological correlates of long-term substance abuse and to discuss the findings within the context of premorbid vulnerabilities, comorbidity and adolescent neurodevelopment. The authors critically review key findings from the neuropsychological literature related to the long-term sequelae of alcohol, cannabis, inhalant, opiates, psychostimulants and ecstasy use. Leading electronic databases such as PubMed were searched to identify relevant studies published in the past 20 years. References identified from bibliographies of pertinent articles and books in the field were also collected and selectively reviewed. Across substances, individuals with long-term abuse consistently demonstrate neuropsychological impairments of executive (inhibitory) control, working memory and decision making, together with neurobiological abnormalities involving frontotemporal and basal ganglia circuits. In some instances these deficits are dose dependent, implying that they are a direct consequence of prolonged drug exposure. However, comorbid behavioural, personality and mental health problems are common among drug-using populations and are associated with similar neuropsychological deficits. Presented herein is a neuropsychological model of addictive behaviour that highlights the complex interplay between cognition, brain maturation, psychopathology and drug exposure.