Acute and chronic effects of cannabinoids on human brain: gene-environment interactions related to psychiatric disorders

Abstract

1) Introduction

Cannabis use has been associated to mental health problems and worsened outcome of established psychiatric disorders. Disturbances of the endocannabinoid system may be responsible for long-lasting effects, such as neuropsychological deficits and morphological brain alterations. As not all the exposed individuals are equally affected, proneness to cannabis induced impairment may rely on key factors such as age of onset, cannabis use parameters and genetic background.

The aim of the present thesis is to expand current knowledge of the effects of cannabinoids, while assessing gene-environment interactions that are relevant for psychiatric disorders, based on the following hypothesis:

- Cannabis use in first-episode psychosis would be associated with worse outcome regarding readmission rates (Chapter 3). - Acute and chronic cannabis use would be associated with alterations on brain function and structure in key areas relevant for psychiatric disorders (Chapters 4-5). - Early-onset chronic cannabis users would show morphological brain alterations compared to non-using controls, and variation in the dopamine-regulating genes would result in diverse liability to experience cannabis-related brain impairment (Chapters 6-7).

2) Methods

We assessed a cohort of 58 first-episode psychosis patients. The main outcome was the time until first readmission. All subjects were interviewed using the Structured Clinical Interview SCIO-I, the Positive and Negative Syndrome Scale (PANSS) and the Dartmouth Assessment of Lifestyle Inventory (DALI) scale. The subjects also underwent blood and urine sampling for drug use (Chapter 3).

In addition, we conducted two systematic literature reviews in accordance with PRISMA guidelines. Chapter 4 included 43 neuroimaging studies of experimental administration of cannabinoids involving animals naive to cannabinoids and naive/occasional cannabis users. Chapter 5 considered 4S neuroimaging studies involving chronic cannabis users with a matched control group.

Finally, we performed a case-control study in male Caucasians, 30 early-onset chronic cannabis users and 29 age-, education- and intelligence-matched non-using controls. All subjects were assessed by a structured interview (PRISM). Catechol-a-methyltransferase (COMT Val(158)Met] and dopamine transporter (DATI-VNTR) genotyping were performed. MRI data was analysed by VBM (Chapter 6) and manual tracing of the hippocampus via well-validated methods (Chapter 7).

3) Results

Cannabis was the most common drug found in the first-episode psychosis cohort, either in urinalysis (38%) or self-reported (50%). Both the DALI cannabis/cocaine subscale (p=0.002) and urinalysis for cannabis (p=0.02) were associated with increased readmission risk in survival curves. The DALI cannabis/cocaine subscale at baseline was a significant predictor of readmission over the study period (HR = 4.5: 95% CI = 1.1 to 18.7; p=0.036) after controlling for potential confounders (Chapter 3).

Studies included in Chapter 4 showed that acute administration of cannabinoids modulate resting state activity and alter neural activity during performance of several cognitive tasks in areas related with reward and psychiatric disorders. Chapter 5 indicated that chronic cannabis use is associated with alterations in brain function and structure, particularly in medial temporal regions.

In the case-control study, chronic cannabis users showed morphologic brain alterations that were differently influenced by the COMT and DATI genotypes compared to controls. Variation in the COMT genotype affected the bilateral ventral caudate nucleus and left amygdala in both groups in an opposite direction (Chapter 6). Chapter 7 expanded these results by showing that COMT and DATI genes interacted with each other moderating individual differences also in the hippocampal volume.

4) Conclusion

Together, these results proVide support for endocannabinoid Involvement in the outcome of psychiatric disorders, as well as in the control of different cognitive functions, dopamine release and brain volume. Findings also provide evidence that dopamine-regulating genes may playa particular role in the sensitivity to the effects of cannabis on brain morphology, providing further insights into the mechanisms of cannabis-related brain impairment and genetic vulnerability.

L'ús de cànnabis pot comportar l'aparició de trastorns mentals i un pitjor curs dels trastorns psiquiàtrics establerts. Alteracions del sistema endocannabinoid endogen podrien ser responsables també dels efectes a llarg termini associats amb el consum d'aquesta substància, com son les alteracions en la funció i estructura cerebral. Donat que no tots els individus es veuen igualment afectats, la probabilitat de patir danys associats al consum de cànnabis podria recaure en diversos factors clau, com són l'edat d'inici, els paràmetres de consum i aspectes relacionats amb la vulnerabilitat genètica individual. Aquesta tesi té com a objectiu eixamplar el coneixement actual sobre els efectes aguts i crònics dels cannabinoids, tot avaluant interaccions gen-ambient que són rellevants pels trastorns psiquiàtrics. Aquest objectiu s'assoleix a través de l'estudi de les conseqüències de l'ús de drogues d'abus en una cohort de primers episodis psicòtics (Capítol 3): dues revisions sistemàtiques de la literatura que inclouen estudis de neuroimatge sobre l'administració experimental de cannabinoids en animals no tractats prèviament i consumidors puntuals/ocasionals de cànnabis (Capítol 4), i estudis de neuroimatge funcional i estructural en consumidors crònics de cànnabis i un grup control aparellat (Capítol 5); i posteriorment per mitjà d'Un estudi cas-control sobre la influència dels gens reguladors de la dopamina ((catecol-O-metiltransferasa (COMT) Ya11S8Met) i transportador de la dopamina (DAT1•YNTR)] en l'estructura cerebral de consumidors crònics de cànnabis d'inici temprà comparats amb controls sans aparellats no consumidors. En conjunt, els resultats presentats en aquesta tesi donen suport a la participació del sistema endocannabinoid en el curs dels trastorns mentals, aixf com en el control de diverses funcions cognitives, modulació de dopamina i volum cerebral. Els resultats també demostren que els gens reguladors de la dopamina poden tenir un paper rellevant en la sensibilitat als efectes del cànnabis en la morfologia cerebral, proporcionant nous coneixements sobre el mecanismes subjacents al dany cerebral induït per cànnabis i sobre aspectes de vulnerabilitat genètica.