Dataset Information

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

ABSTRACT:

Background

Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife.

Methods

We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances.

Results

Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning-predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco.

Conclusions

These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.

SUBMITTER: Knodt AR

PROVIDER: S-EPMC9637748 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

Knodt Annchen R AR Meier Madeline H MH Ambler Antony A Gehred Maria Z MZ Harrington HonaLee H Ireland David D Poulton Richie R Ramrakha Sandhya S Caspi Avshalom A Moffitt Terrie E TE Hariri Ahmad R AR

Biological psychiatry 20220622 11

<h4>Background</h4>Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a ...[more]

PMID: 36008158

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Project description:BackgroundCannabis is often characterised as a young person's drug. However, people who began consuming cannabis in the 1970s and 1980s are no longer young and some have consumed it for many years. This study tested the preregistered hypothesis that long-term cannabis users show accelerated biological ageing in midlife and poorer health preparedness, financial preparedness, and social preparedness for old age.MethodsIn this longitudinal study, participants comprised a population-representative cohort of 1037 individuals born in Dunedin, New Zealand, between April, 1972, and March, 1973, and followed to age 45 years. Cannabis, tobacco, and alcohol use and dependence were assessed at ages 18 years, 21 years, 26 years, 32 years, 38 years, and 45 years. Biological ageing and health, financial, and social preparedness for old age were assessed at age 45 years. Long-term cannabis users were compared using independent samples t tests with five groups: lifelong cannabis non-users, long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. In addition, regression analyses tested dose-response associations for continuously measured persistence of cannabis dependence from age 18 years to 45 years, with associations adjusted for sex, childhood socioeconomic status, childhood IQ, low childhood self-control, family substance dependence history, and persistence of alcohol, tobacco, and other illicit drug dependence.FindingsOf 997 cohort members still alive at age 45 years, 938 (94%) were assessed at age 45 years. Long-term cannabis users showed statistically significant accelerated biological ageing and were less equipped to manage a range of later-life health, financial, and social demands than non-users. Standardised mean differences between long-term cannabis users and non-users were large: 0·70 (95% CI 0·46 to 0·94; p<0·0001) for biological ageing, -0·72 (-0·96 to -0·49, p<0·0001) for health preparedness, -1·08 (-1·31 to -0·85; p<0·0001) for financial preparedness, and -0·59 (-0·84 to -0·34, p<0·0001) for social preparedness. Long-term cannabis users did not fare better than long-term tobacco or alcohol users. Tests of dose-response associations suggested that cannabis associations could not be explained by the socioeconomic origins, childhood IQ, childhood self-control, and family substance-dependence history of long-term cannabis users. Statistical adjustment for long-term tobacco, alcohol, and other illicit drug dependence suggested that long-term cannabis users' tendency toward polysubstance dependence accounted for their accelerated biological ageing and poor financial and health preparedness, although not for their poor social preparedness (β -0·10, 95% CI -0·18 to -0·02; p=0·017).InterpretationLong-term cannabis users are underprepared for the demands of old age. Although long-term cannabis use appears detrimental, the greatest challenge to healthy ageing is not use of any specific substance, but rather the long-term polysubstance use that characterises many long-term cannabis users. Substance-use interventions should include practical strategies for improving health and building financial and social capital for healthy longevity.FundingThe National Institute on Aging and the UK Medical Research Council. The Dunedin Research Unit is supported by the New Zealand Health Research Council and the New Zealand Ministry of Business, Innovation and Employment.

Project description:ImportanceCannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain.ObjectiveTo investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers.Design, setting, and participantsThis cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.Main outcomes and measuresTotal distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured.ResultsIn total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users.Conclusions and relevanceThe results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.

Project description:Cannabis is one of the most used and commodified illicit substances worldwide, especially among young adults. The neurobiology mechanism of cannabis is yet to be identified particularly in youth. The purpose of this study was to concurrently measure alterations in brain structural and functional connectivity in cannabis users using resting-state functional magnetic resonance images (rs-fMRI) and diffusion-weighted images (DWI) from a group of 73 cannabis users (age 22-36, 19 female) in comparison with 73 healthy controls (age 22-36, 14 female) from Human Connectome Project (HCP). Several significant differences were observed in local structural/functional network measures (e.g. degree and clustering coefficient), being prominent in the insular and frontal opercular cortex and lateral/medial temporal cortex. The rich-club organization of structural networks revealed a normal trend, distributed within bilateral frontal, temporal and occipital regions. However, minor differences were found between the two groups in the superior and inferior temporal gyri. Functional rich-club nodes were mostly located within parietal and posterior areas, with minor differences between the groups found mainly in the centro-temporal and parietal regions. Regional network measures of structural/functional networks were associated with times used cannabis (TUC) in several regions. Although the structural/functional network in both groups showed small-world property, no differences between cannabis users and healthy controls were found regarding the global network measures, showing no association with cannabis use. After FDR correction, all of the significant associations between network measures and TUC were found to be insignificant, except for the association between degree and TUC within the presubiculum region. To recap, our findings revealed alterations in local topological properties of structural and functional networks in cannabis users, although their global brain network organization remained intact.

Project description:Background:Research on cannabis has focused on lifetime use or regular/heavy use (i.e., daily or almost daily). Regular, albeit not necessarily daily, cannabis use has received less scientific attention. Objectives:This study aims to identify demographic and personality factors associated with recurrent cannabis use (i.e., cannabis usage 5 to 50 times in the last six months) and to investigate the relationship between cannabis use and use of other substances. Methods:Public and private university students (N = 11,236) in Bergen, Norway, participated in an online survey during autumn 2015. Binary logistic regression was run to identify individual characteristics related to recurrent cannabis use. Chi-square tests were conducted to investigate differences in substance use (alcohol, nicotine, and illicit drugs) between recurrent cannabis users and cannabis abstainers/low-frequency users. Results:A total of 4.0% of the students reported recurrent cannabis use. Students born in North America, non-Christians (compared to non-religious students), and men were more likely to be recurrent users. Recurrent cannabis users scored higher on extroversion and intellect/imagination compared to abstainers/low-frequency users. Male and female recurrent cannabis users had somewhat different characteristics (e.g., agreeableness scores were negatively associated with recurrent use among females but not among males). Recurrent cannabis use was overall strongly associated with polysubstance use. Conclusions:The prevalence of recurrent cannabis use among Norwegian students is low. Recurrent cannabis use seems more prevalent among individuals marked by extroversion and intellect/imagination, which supports the notion of cannabis use as a social activity for individuals identifying themselves as outgoing and unconventional. Cannabis use among students seems strongly associated with use of other substances, suggesting that cannabis should not be considered a replacement drug.

Dataset Information

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

Background

Methods

Results

Conclusions

Publications

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

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