Consecuencias del consumo de cannabis. Revisión narrativa / Consequences of cannabis use. narrative review

El cannabis es la tercera droga más consumida a nivel mundial, tras el alcohol y el tabaco. En el entorno actual, con presiones para su legalización, se realizó una revisión narrativa en base a la literatura reciente, para actualizar las evidencias sobre los efectos de su consumo con fines recreativos. Se seleccionaron 19 artículos sobre consecuencias a nivel orgánico y 6 sobre acciones nocivas en la esfera psiquiátrica. A nivel orgánico, existe asociación entre el consumo de cannabis y patología cardiovascular (IAM, ACV, arritmias y con muerte súbita); a nivel respiratorio, hay asociación con bronquitis crónica y con la alteración de los volúmenes pulmonares. Se ha visto riesgo oncológico con el cáncer testicular no seminoma y más probabilidad de desarrollar cáncer primario de orofaringe. En el embarazo, hay asociación con el riesgo de bajo peso al nacer y aumento de ingresos en UCI de los neonatos. A nivel cognitivo, se han demostrado deficiencias en la memoria, atención y procesamiento, así como a la hora de conducir. A nivel psiquiátrico, se observa una relación del consumo con el desarrollo de esquizofrenia, psicosis y ansiedad, junto con depresión, sin que su frecuencia y presentación clínica se hayan odificado en los últimos 5 años. (AU)

Cannabis is the third most widely used drug worldwide, after alcohol and tobacco. In the current environment, with pressures for its legalisation, a narrative review was carried out based on recent literature to update the evidence on the effects of its recreational use. Nineteen articles on consequences at the organ level and six on harmful actions in the psychiatric sphere were selected. At the organ level, there is an association between cannabis use and cardiovascular pathology (AMI, stroke, arrhythmias and sudden death); at the respiratory level, there is an association with chronic bronchitis and altered lung volumes. Oncological risk has been seen with non-seminoma testicular cancer and increased likelihood of developing primary oropharyngeal cancer. In pregnancy, there is an association with the risk of low birth weight and increased neonatal ICU admissions. At the cognitive level, impairments in memory, attention and processing, as well as in driving have been demonstrated. At the psychiatric level, a relationship between cannabis use and the development of schizophrenia, psychosis and anxiety, together with depression, has been observed, with no change in their frequency and clinical presentation in the last 5 years. (AU)

Neurostructural Correlates of Cannabis Use in Adolescent Bipolar Disorder.

BACKGROUND: Little is known regarding the association of cannabis use with brain structure in adolescents with bipolar disorder (BD). This subject is timely, given expanded availability of cannabis contemporaneously with increased social acceptance and diminished societal constraints to access. Therefore, we set out to examine this topic in a sample of adolescents with BD and healthy control (HC) adolescents. METHODS: Participants included 144 adolescents (47 BD with cannabis use [BDCB+; including 13 with cannabis use disorder], 34 BD without cannabis use [BDCB-], 63 HC without cannabis use) ages 13-20 years. FreeSurfer-processed 3T MRI with T1-weighted contrast yielded measures of cortical thickness, surface area (SA), and volume. Region of interest (amygdala, hippocampus, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) analyses and exploratory vertex-wise analysis were undertaken. A general linear model tested for between-group differences, accounting for age, sex, and intracranial volume. RESULTS: Vertex-wise analysis revealed significant group effects in frontal and parietal regions. In post-hoc analyses, BDCB+ exhibited larger volume and SA in parietal regions, and smaller thickness in frontal regions, relative to HC and BDCB-. BDCB- had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. There were no significant region of interest findings after correcting for multiple comparisons. CONCLUSION: This study found that cannabis use is associated with differences in regional brain structure among adolescents with BD. Future prospective studies are necessary to determine the direction of the observed association and to assess for dose effects.

Recent cannabis use is associated with smaller hippocampus volume: High-resolution segmentation of structural subfields in a large non-clinical sample.

There is mixed evidence that individuals who use cannabis have reduced hippocampal and amygdalar gray matter volume, potentially because of small sample sizes and imprecise morphological characterization. New automated segmentation procedures have improved the measurement of these structures and allow better examination of their subfields, which have been linked to distinct aspects of memory and emotion. The current study applies this new segmentation procedure to the Human Connectome Project Young Adult dataset (N = 1080) to investigate associations of cannabis use with gray matter volume in the hippocampus and amygdala. Results revealed significant bilateral inverse associations of hippocampal volume with recent cannabis use (THC+ urine drug screen; P < .005). Hippocampal subfield analyses indicated these associations were primarily driven by the head of the hippocampus, the first section of the cornu amonis (CA1), the subicular complex, and the molecular layer of the hippocampus. No associations were detected for age of cannabis initiation, the frequency of cannabis use across the lifespan, or the lifetime presence of cannabis use disorder. In one of the largest studies to date, these results support the hypothesis that recent cannabis use is linked to reduced hippocampal volume, but that this effect may dissipate following prolonged abstinence. Furthermore, these results clarify the specific subfields which may be most associated with recent cannabis use.

Microstructural brain abnormalities in HIV+ individuals with or without chronic marijuana use.

OBJECTIVE: Cognitive deficits and microstructural brain abnormalities are well documented in HIV-positive individuals (HIV+). This study evaluated whether chronic marijuana (MJ) use contributes to additional cognitive deficits or brain microstructural abnormalities that may reflect neuroinflammation or neuronal injury in HIV+. METHOD: Using a 2 × 2 design, 44 HIV+ participants [23 minimal/no MJ users (HIV+), 21 chronic active MJ users (HIV + MJ)] were compared to 46 seronegative participants [24 minimal/no MJ users (SN) and 22 chronic MJ users (SN + MJ)] on neuropsychological performance (7 cognitive domains) and diffusion tensor imaging metrics, using an automated atlas to assess fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities, in 18 cortical and 4 subcortical brain regions. RESULTS: Compared to SN and regardless of MJ use, the HIV+ group had lower FA and higher diffusivities in multiple white matter and subcortical structures (p < 0.001-0.050), as well as poorer cognition in Fluency (p = 0.039), Attention/Working Memory (p = 0.009), Learning (p = 0.014), and Memory (p = 0.028). Regardless of HIV serostatus, MJ users had lower AD in uncinate fasciculus (p = 0.024) but similar cognition as nonusers. HIV serostatus and MJ use showed an interactive effect on mean diffusivity in the right globus pallidus but not on cognitive function. Furthermore, lower FA in left anterior internal capsule predicted poorer Fluency across all participants and worse Attention/Working Memory in all except SN subjects, while higher diffusivities in several white matter tracts also predicted lower cognitive domain Z-scores. Lastly, MJ users with or without HIV infection showed greater than normal age-dependent FA declines in superior longitudinal fasciculus, external capsule, and globus pallidus. CONCLUSIONS: Our findings suggest that, except in the globus pallidus, chronic MJ use had no additional negative influence on brain microstructure or neurocognitive deficits in HIV+ individuals. However, lower AD in the uncinate fasciculus of MJ users suggests axonal loss in this white matter tract that connects to cannabinoid receptor rich brain regions that are involved in verbal memory and emotion. Furthermore, the greater than normal age-dependent FA declines in the white matter tracts and globus pallidus in MJ users suggest that older chronic MJ users may eventually have lesser neuronal integrity in these brain regions.

Cannabis use in patients with early psychosis is associated with alterations in putamen and thalamic shape.

Around half of patients with early psychosis have a history of cannabis use. We aimed to determine if there are neurobiological differences in these the subgroups of persons with psychosis with and without a history of cannabis use. We expected to see regional deflations in hippocampus as a neurotoxic effect and regional inflations in striatal regions implicated in addictive processes. Volumetric, T1w MRIs were acquired from people with a diagnosis psychosis with (PwP + C = 28) or without (PwP - C = 26) a history of cannabis use; and Controls with (C + C = 16) or without (C - C = 22) cannabis use. We undertook vertex-based shape analysis of the brainstem, amygdala, hippocampus, globus pallidus, nucleus accumbens, caudate, putamen, thalamus using FSL FIRST. Clusters were defined through Threshold Free Cluster Enhancement and Family Wise Error was set at p < .05. We adjusted analyses for age, sex, tobacco and alcohol use. The putamen (bilaterally) and the right thalamus showed regional enlargement in PwP + C versus PwP - C. There were no areas of regional deflation. There were no significant differences between C + C and C - C. Cannabis use in participants with psychosis is associated with morphological alterations in subcortical structures. Putamen and thalamic enlargement may be related to compulsivity in patients with a history of cannabis use.

Associations between adolescent cannabis use frequency and adult brain structure: A prospective study of boys followed to adulthood.

BACKGROUND: Few studies have tested the hypothesis that adolescent cannabis users show structural brain alterations in adulthood. The present study tested associations between prospectively-assessed trajectories of adolescent cannabis use and adult brain structure in a sample of boys followed to adulthood. METHODS: Data came from the Pittsburgh Youth Study - a longitudinal study of ˜1000 boys. Boys completed self-reports of cannabis use annually from age 13-19, and latent class growth analysis was used to identify different trajectories of adolescent cannabis use. Once adolescent cannabis trajectories were identified, boys were classified into their most likely cannabis trajectory. A subset of boys (n = 181) subsequently underwent structural neuroimaging in adulthood, when they were between 30-36 years old on average. For this subset, we grouped participants according to their classified adolescent cannabis trajectory and tested whether these groups showed differences in adult brain structure in 14 a priori regions of interest, including six subcortical (volume only: amygdala, hippocampus, nucleus accumbens, caudate, putamen, and pallidum) and eight cortical regions (volume and thickness: superior frontal gyrus; caudal and rostral middle frontal gyrus; inferior frontal gyrus, separated into pars opercularis, pars triangularis, and pars orbitalis; lateral and medial orbitofrontal gyrus). RESULTS: We identified four adolescent cannabis trajectories: non-users/infrequent users, desisters, escalators, and chronic-relatively frequent users. Boys in different trajectory subgroups did not differ on adult brain structure in any subcortical or cortical region of interest. CONCLUSIONS: Adolescent cannabis use is not associated with structural brain differences in adulthood.

Marijuana use and major depressive disorder are additively associated with reduced verbal learning and altered cortical thickness.

Marijuana (MJ) use and major depressive disorder (MDD) have both been associated with deficits in verbal learning and memory as well as structural brain abnormalities. It is not known if MJ use by those with MDD confers additional impairment. The goal of this study was to examine unique and combined effects of MDD and MJ use on verbal memory and brain structure. Young adults (n=141) aged 18-25 years with MJ use and no lifetime MDD (MJ, n=46), MDD and no MJ use (MDD, n=23), MJ use and lifetime MDD (MDD+MJ, n=24), and healthy controls without MDD or MJ use (CON, n=48) were enrolled. Participants completed the California Verbal Learning Test, Second Edition (CVLT-II), a measure of verbal learning and memory. A sub-sample of 82 participants also underwent a structural magnetic resonance imaging (MRI) scan. Group differences in CVLT-II performance, cortical thickness, and hippocampal volume were assessed. We found an additive effect of MDD and MJ on memory recall. Only MDD, but not MJ, was associated with poorer initial learning, fewer words recalled, more intrusion errors, and lower percent retention. There was also an additive effect of MDD and MJ use on reduced cortical thickness in the middle temporal gyrus. Findings indicate that MJ use and MDD have additive adverse associations with verbal recall and cortical thickness in the middle temporal gyrus, suggesting that MJ use among those with MDD may be contraindicated. Prospective studies are warranted to determine whether this association may be causal.

Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood.

Δ9-tetrahydrocannabinol (THC) consumption during adolescence is reported to be a risk factor for the appearance of psychiatric disorders later in life. The interaction between genetic or environmental events and cannabinoid exposure in the adolescent period can also contribute to exacerbate behavioural deficits in adulthood. Here we investigate the effects of THC treatment as well as the consequences of concomitant THC and stress exposure during adolescence in the extinction of fear memory in adult mice. Adolescent mice treated with THC and exposed to stress exhibit impaired cued fear extinction in adulthood. However, no effect was observed in animals exposed to these two factors separately. Notably, resistance to fear extinction was associated with decreased neuronal activity in the basolateral amygdala (BLA) and the infralimbic prefrontal cortex, suggesting a long-term dysregulation of the fear circuit. These changes in neuronal activation were paralleled with structural plasticity alterations. Indeed, an increase of immature dendritic spines in pyramidal neurons of the BLA was revealed in mice simultaneously exposed to THC and stress. Corticosterone levels were also enhanced after the cued fear conditioning session in the same experimental group. These results show that an interaction between cannabis exposure and stress during adolescence may lead to long-term anxiety disorders characterized by the presence of pathological fear.

Alteration to hippocampal volume and shape confined to cannabis dependence: a multi-site study.

Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis.

Social Factors and Animal Models of Cannabis Use.

Cannabis, or the dried leaves, stems, and seeds of the hemp plant Cannabis sativa, is the most widely used illicit drug in America. Typically smoked, vaporized or ingested orally, cannabis is used primarily for recreational purposes, though a few synthetic cannabinoids have been approved for medicinal treatments. Psychoactive cannabinoids, or the pharmacologically active compounds within cannabis, are responsible for producing the infamous "high" sensation, characterized by feelings of euphoria and relaxation, though can also provoke hallucinations, paranoia and anxiety. Cannabinoids act on G-protein coupled receptors in the brain, primarilyCB1 receptors, that typically decrease neural activity and modulate transmitter release. Compared to other drugs of abuse, cannabis use has minimal health risks and almost no potential for fatal overdose, though the trademark method of administration (smoking) has detrimental consequences. Chronic heavy use can also lead to changes in memory, cognitive deficits, psychosis and dependence. Up to 9% of users can develop a cannabis dependence, characterized by a characteristic withdrawal syndrome. The growing prevalence of cannabis use has spurred the development of animals models to research the neurobehavioral basis of cannabis use. Traditional animal models of drug abuse (i.e., conditioned place preference (CPP) and self-administration) have historically struggled to establish rewarding or reinforcing effects of individual cannabinoid molecules. Decades of research have been needed to reveal the appropriate dosage and conditions to promote reward and reinforcement in animal models. While the field has made great strides in elucidating the mechanisms involved in behavioral pharmacology cannabinoids, the social aspects of cannabis use remains underrepresented in animal models. Social interactions are vital to the initiation and continuation of cannabis use in humans, and this component has yet to be accurately captured in current animal models.

Role of orbitofrontal sulcogyral pattern on lifetime cannabis use and depressive symptoms.

Orbitofrontal cortex (OFC) sulcogyral patterns are stable morphological variations established early in life. They consist of three distinct pattern types, with Type III in particular being associated with poor regulatory control (e.g., high sensation seeking and negative emotionality, low constraint), which may confer risk for earlier onset of cannabis (CB) use and greater use in later life. The OFC sulcogyral pattern may therefore be a stable trait marker in understanding individual differences in substance-use vulnerability and associated affective disturbances in users. In a large multisite cross-sectional study, we compared OFC pattern type distribution between 128 healthy controls (HC) and 146 CB users. Within users (n=140), we explored the association between OFC pattern type and CB use level, and subsequently if level of CB use informed by OFC pattern type may mediate disturbances in affective tone, as indexed by depressive symptoms. While OFC pattern distribution did not distinguish between HC and CB groups, it informed greater lifetime use within users. Specifically, CB users with pattern Type III in the right OFC tended to use more CB over their lifetime, than did CB users with pattern Type I or II. Greater lifetime CB use was subsequently associated with higher depressive symptoms, such that it mediated an indirect association between right OFC pattern Type III and higher depressive symptoms. The present study provides evidence for neurobiological differences, specifically sulcogyral pattern of the OFC, to modulate level of CB use, which may subsequently influence the expression of depressive symptoms.

Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults.

BACKGROUND AND AIMS: Chronic alcohol use is associated with lower gray matter volume, and we reported recently that alcohol use showed negative associations with widespread gray matter (GM) volume even among young adults. The current study aimed to test the strength of association between (1) alcohol use and GM volume; (2) alcohol use and white matter (WM) integrity; (3) cannabis use and GM volume; and (4) cannabis use and WM integrity among adults and adolescents. DESIGN AND SETTING: General linear models within large pooled cross-sectional samples of adolescents and adults who had participated in studies collecting substance use and neuroimaging data in the southwestern United States. PARTICIPANTS: The current analysis included adults aged 18-55 years (n = 853) and adolescents aged 14-18 years (n = 439) with a range of alcohol and cannabis use. MEASUREMENTS: The dependent variable was GM volume or WM integrity, with key predictors of alcohol use [Alcohol Use Disorders Identification Test (AUDIT) score] and cannabis use (past 30-day use). FINDINGS: Alcohol use showed large clusters of negative associations (ηp2  = 0.028-0.145, P < 0.001) with GM volume among adults and to a lesser extent (one cluster; ηp2  = 0.070, P < 0.05) among adolescents. Large clusters showed significant associations (ηp2  = 0.050-0.124, P < 0.001) of higher alcohol use with poorer WM integrity, whereas adolescents showed no significant associations between alcohol use and WM. No associations were observed between structural measures and past 30-day cannabis use in adults or adolescents. CONCLUSIONS: Alcohol use severity is associated with widespread lower gray matter volume and white matter integrity in adults, and with lower gray matter volume in adolescents.

Discriminative Properties of Hippocampal Hypoperfusion in Marijuana Users Compared to Healthy Controls: Implications for Marijuana Administration in Alzheimer's Dementia.

BACKGROUND: Few studies have evaluated the impact of marijuana use on regional cerebral blood flow. OBJECTIVE: To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer's disease pathology, are abnormal in marijuana users compared to controls. METHOD: Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n = 982) were compared to controls (n = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n = 436) with reduced psychiatric co-morbidities. RESULTS: Marijuana users showed lower cerebral perfusion on average (p < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls. CONCLUSION: Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer's disease pathology. This study raises the possibility of deleterious brain effects of marijuana use.