Long-term Heavy Cannabis Users Research Articles

P.6.e.004 - Cannabis dependence and the brain reward system: disentangling the role of exposure and addiction related effects

Evidence that long-term cannabis use may be hazardous to white matter in the developing brain has been accumulating, with early onset use in particular thought to impair structural morphology and integrity, during the critical neurodevelopment occurring in adolescence. We found specific localized axonal connectivity disturbances in adult long-term heavy cannabis users, with 84–88% reductions in streamlines in the fimbria of the hippocampus, and commissural fibers extending to the precuneus. White matter integrity within these fiber bundles was associated with the age of onset of cannabis use. The endocannabinoid system is critically involved in axonal growth in the developing brain; mechanisms underlying axonal morphological alterations following exposure to cannabis in utero have been identified. Mechanisms that may be specifically perturbed by cannabis use impacting the neurodevelopment and brain maturational processes that occur during adolescence require further research. Dysfunctional connectivity may underlie a wide range of cognitive disturbances and psychological symptoms, including vulnerability to psychosis, depression, and anxiety disorders, all of which are significant public health concerns.

Abnormal medial prefrontal cortex activity in heavy cannabis users during conscious emotional evaluation.

Long-term heavy cannabis users (cannabis users) who are not acutely intoxicated have diminished subconscious neural responsiveness to affective stimuli. This study sought to determine if abnormal processing extends to the conscious evaluation of emotional stimuli. Functional magnetic resonance imaging (fMRI) was used to examine brain activity as cannabis users (N = 16) and non-cannabis-using controls (N = 17) evaluated and categorized standardized International Affective Picture System (IAPS) stimuli. Individual judgments were used to isolate activity during the evaluation of emotional (i.e., emotional evaluation) or neutral (i.e., neutral evaluation) stimuli. Within- and between-group analyses were performed. Both groups judged the same stimuli as emotional and had activations in visual, midbrain, and middle cingulate cortices during emotional evaluation, relative to neutral. Within-group analyses also revealed amygdalar and inferior frontal gyrus activations in controls, but not cannabis users, and medial prefrontal cortex (mPFC) deactivations in cannabis users, but not controls, during emotional evaluation, relative to neutral. Between-group comparisons found that mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users, relative to controls. Abnormal neural processing of affective content extends to the level of consciousness in cannabis users. The hypoactive mPFC responses observed resembles the attenuated mPFC responses found during increased non-affective cognitive load in prior research. These findings suggest that abnormal mPFC singling in cannabis users during emotional evaluation might be associated with increased non-affective cognitive load.

Cerebellar white-matter changes in cannabis users with and without schizophrenia

The cerebellum is rich in cannabinoid receptors and implicated in the neuropathology of schizophrenia. Long-term cannabis use is associated with functional and structural brain changes similar to those evident in schizophrenia, yet its impact on cerebellar structure has not been determined. We examined cerebellar grey and white matter in cannabis users with and without schizophrenia. Seventeen patients with schizophrenia and 31 healthy controls were recruited; 48% of the healthy group and 47% of the patients were long-term heavy cannabis users (mean 19.7 and 17.9 years near daily use respectively). Cerebellar measures were extracted from structural 3-T magnetic resonance imaging (MRI) scans using semi-automated methods, and examined using analysis of covariance (ANCOVA) and correlational analyses. Cerebellar white-matter volume was reduced in cannabis users with and without schizophrenia compared to healthy non-users, by 29.7% and 23.9% respectively, and by 17.7% in patients without cannabis use. Healthy cannabis users did not differ in white-matter volume from either of the schizophrenia groups. There were no group differences in cerebellar grey matter or total volumes. Total cerebellar volume decreased as a function of duration of cannabis use in the healthy users. Psychotic symptoms and illness duration correlated with cerebellar measures differentially between patients with and without cannabis use. Long-term heavy cannabis use in healthy individuals is associated with smaller cerebellar white-matter volume similar to that observed in schizophrenia. Reduced volumes were even more pronounced in patients with schizophrenia who use cannabis. Cannabis use may alter the course of brain maturational processes associated with schizophrenia.

Regional Brain Abnormalities Associated With Long-term Heavy Cannabis Use

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. 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. Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. Participants were recruited from the general community and underwent imaging at a hospital research facility. 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). Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. 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. 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.

Multiple Sclerosis, Cannabinoids, and Cognition

Multiple Sclerosis, Cannabinoids, and Cognition

Psychophysiological responses to drug‐associated stimuli in chronic heavy cannabis use

Due to learning processes originally neutral stimuli become drug-associated and can activate an implicit drug memory, which leads to a conditioned arousing 'drug-seeking' state. This condition is accompanied by specific psychophysiological responses. The goal of the present study was the analysis of changes in cortical and peripheral reactivity to cannabis as well as alcohol-associated pictures compared with emotionally significant drug-unrelated and neutral pictures in long-term heavy cannabis users. Participants were 15 chronic heavy cannabis users and 15 healthy controls. Verbal reports as well as event-related potentials of the electroencephalogram and skin conductance responses were assessed in a cue-reactivity paradigm to determine the psychophysiological effects caused by drug-related visual stimulus material. The evaluation of self-reported craving and emotional processing showed that cannabis stimuli were perceived as more arousing and pleasant and elicited significantly more cannabis craving in cannabis users than in healthy controls. Cannabis users also demonstrated higher cannabis stimulus-induced arousal, as indicated by significantly increased skin conductance and a larger late positivity of the visual event-related brain potential. These findings support the assumption that drug-associated stimuli acquire increased incentive salience in addiction history and induce conditioned physiological patterns, which lead to craving and potentially to drug intake. The potency of visual drug-associated cues to capture attention and to activate drug-specific memory traces and accompanying physiological symptoms embedded in a cycle of abstinence and relapse--even in a 'so-called' soft drug--was assessed for the first time.

Impaired verbal learning and reduced medial temporal volumes in long-term heavy cannabis users

Event Abstract Back to Event Impaired verbal learning and reduced medial temporal volumes in long-term heavy cannabis users Murat Yücel1, 2*, M. Solowij3, 4, S. Whittle1, 2, C. Respondek3, Alex Fornito2, C. Pantelis2 and D. I. Lubman1 1 ORYGEN Research Centre, Australia 2 The University of Melbourne and Melbourne Health , Australia 3 University of Wollongong , Australia 4 Schizophrenia Research Institute, Australia Background: Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term impact on the human brain. Our aim was to determine whether long-term and heavy cannabis use is associated with verbal learning deficits and gross anatomical abnormalities in two cannabinoid receptor rich regions of the brain, the hippocampus and amygdala. Method: A cross-sectional design using high-resolution (3-Tesla) structural magnetic resonance imaging (MRI) was utilised. Participants were recruited from the general community and scanned at a hospital research facility. Fifteen carefully selected long-term (>10 years duration) and heavy (>5 joints per day) cannabis-using males (mean age 39.8 years; 19.7 years of regular use) with no history of polydrug abuse or neurological/mental disorder, and 16 matched non-using healthy volunteers (mean age 36.4 years). Volumetric measures of hippocampus and 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=0.001) with a relatively (and significantly; P=0.018) greater magnitude of reduction in the former (12.0% in hippocampus vs 7.1% in amygdala). Left hippocampal volume was inversely associated with cumulative dose of cannabis use over the previous 10 years (P=0.014), as well as subthreshold positive psychotic symptoms (P<0.001). Positive symptom scores were also associated with cumulative dose of cannabis used (P= 0.048). While cannabis users performed significantly worse than controls on verbal learning (P= 0.0005), this did not correlate with regional brain volumes in either group. Conclusions: Our results provide new evidence of dose-related structural abnormalities in the hippocampus and amygdala of long-term heavy cannabis users, and corroborate similar findings within the animal literature. These findings indicate that heavy daily cannabis use over protracted periods exerts harmful effects on brain tissue and mental health. Conference: 10th International Conference on Cognitive Neuroscience, Bodrum, Turkey, 1 Sep - 5 Sep, 2008. Presentation Type: Oral Presentation Topic: Memory & Learning Citation: Yücel M, Solowij M, Whittle S, Respondek C, Fornito A, Pantelis C and Lubman DI (2008). Impaired verbal learning and reduced medial temporal volumes in long-term heavy cannabis users. Conference Abstract: 10th International Conference on Cognitive Neuroscience. doi: 10.3389/conf.neuro.09.2009.01.259 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 09 Dec 2008; Published Online: 09 Dec 2008. * Correspondence: Murat Yücel, ORYGEN Research Centre, Melbourne, VIC., Australia, murat.yucel@monash.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Murat Yücel M. Solowij S. Whittle C. Respondek Alex Fornito C. Pantelis D. I Lubman Google Murat Yücel M. Solowij S. Whittle C. Respondek Alex Fornito C. Pantelis D. I Lubman Google Scholar Murat Yücel M. Solowij S. Whittle C. Respondek Alex Fornito C. Pantelis D. I Lubman PubMed Murat Yücel M. Solowij S. Whittle C. Respondek Alex Fornito C. Pantelis D. I Lubman Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Normative data and discriminant validity of Rey's Verbal Learning Test for the Greek adult population

The present study sought to establish normative and discriminant validity data for Rey's Auditory Verbal Learning Test [Rey, A. (1964). L ‘examen clinique en psychologie [Clinical tests in psychology]. Paris: Presses Universitaires de France; Schmidt, M. (1996). Rey auditory verbal learning test: A handbook. Los Angeles, CA: Western Psychological Services] using newly adapted learning lists for the Greek adult population. Applying the procedure suggested by Geffen et al. [Geffen, G., Moar, K. J., O’Hanlon, A. P., Clark, C. R., & Geffen, L. N. (1990). Performance measures of 16–86-year-old males and females on the auditory verbal learning test. The Clinical Neuropsychologist, 4, 45–63] we administered the test to 205 healthy participants, aged 18–78 years and two adult patient groups (long-term cannabis users and HIV symptomatic patients). Stepwise linear regression analyses showed that the variables age, education and gender contributed significantly to most trials of the RAVLT. Performance decreased in an age-dependent manner from young adulthood. Women, young adults and higher educated participants outperformed men, older adults and less educated individuals. The test appears to discriminate adequately between the performance of long-term heavy cannabis users and HIV seropositive symptomatic patients and matched healthy controls, as both patient groups performed more poorly than their respective control group. Normative data stratified by age, gender and education for the Greek adult population is presented for use in research and clinical settings.

Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study

Many neuropsychological studies have documented deficits in working memory among recent heavy cannabis users. However, little is known about the effects of cannabis on brain activity. We assessed brain function among recent heavy cannabis users while they performed a working memory task. Functional magnetic resonance imaging was used to examine brain activity in 12 long-term heavy cannabis users, 6-36 h after last use, and in 10 control subjects while they performed a spatial working memory task. Regional brain activation was analyzed and compared using statistical parametric mapping techniques. Compared with controls, cannabis users exhibited increased activation of brain regions typically used for spatial working memory tasks (such as prefrontal cortex and anterior cingulate). Users also recruited additional regions not typically used for spatial working memory (such as regions in the basal ganglia). These findings remained essentially unchanged when re-analyzed using subjects' ages as a covariate. Brain activation showed little or no significant correlation with subjects' years of education, verbal IQ, lifetime episodes of cannabis use, or urinary cannabinoid levels at the time of scanning. Recent cannabis users displayed greater and more widespread brain activation than normal subjects when attempting to perform a spatial working memory task. This observation suggests that recent cannabis users may experience subtle neurophysiological deficits, and that they compensate for these deficits by "working harder"-calling upon additional brain regions to meet the demands of the task.

Attributes of long-term heavy cannabis users: a case-control study.

Although cannabis is the most widely used illicit drug in the United States, few recent American studies have examined the attributes of long-term heavy cannabis users. Using a case-control design, we obtained psychological and demographic measures on 108 individuals, age 30-55, who had smoked cannabis a mean of 18000 times and a minimum of 5000 times in their lives. We compared these heavy users to 72 age-matched control subjects who had smoked at least once, but no more than 50 times in their lives. We found no significant differences between the two groups on reported levels of income and education in their families of origin. However, the heavy users themselves reported significantly lower educational attainment (P < 0.001) and income (P = 0.003) than the controls, even after adjustment for a large number of potentially confounding variables. When asked to rate the subjective effects of cannabis on their cognition, memory, career, social life, physical health and mental health, large majorities of heavy users (66-90%) reported a 'negative effect'. On several measures of quality of life, heavy users also reported significantly lower levels of satisfaction than controls. Both objective and self-report measures suggest numerous negative features associated with long-term heavy cannabis use. Thus, it seems important to understand why heavy users continue to smoke regularly for years, despite acknowledging these negative effects. Such an understanding may guide the development of strategies to treat cannabis dependence.

Early-onset cannabis use and cognitive deficits: what is the nature of the association?

Background: Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life. Methods: We analyzed neuropsychological test results from 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure, all of whom had undergone a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. We compared early-onset cannabis users with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin. Results: The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late-onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, when we adjusted for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant. Conclusions: Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1) innate differences between groups in cognitive ability, antedating first cannabis use; (2) an actual neurotoxic effect of cannabis on the developing brain; or (3) poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture.

Cognitive functioning of long-term heavy cannabis users seeking treatment.

Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain. To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence. Multisite retrospective cross-sectional neuropsychological study conducted in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between 1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared with 33 nonuser controls. Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence. Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users (P =.001) or controls (P =.005); there was no difference between shorter-term users and controls. Long-term users showed impaired learning (P =.007), retention (P =.003), and retrieval (P =.002) compared with controls. Both user groups performed poorly on a time estimation task (P<.001 vs controls). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use. These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.

Some psychological correlates of long-term heavy cannabis users.

Fifty persons who had all been heavy cannabis users for a long time were given psychological tests measuring psychomotor, perceptual and other variables. Half of these persons were "Charas" smokers, half "Bhang" drinkers. The duration of cannabis use was 4--10 years, with an average daily dose of 150 mg tetrahydrocannabinol. A matched control group of twenty-five persons were given the same tests. Compared with this group, the cannabis users were found to react more slowly, to be poorer in concentration and time estimation, to have higher neuroticism and greater perceptuo-motor disturbance. The higher neuroticism and greater perceptuo-motor disturbance. The Charas smokers were the poorest performers and also showed poor memory, lowered psychomotor activity, and poor size estimation.