Investigating resting-state functional connectivity differences in cannabis use disorder and exploring their mitigation through brief mindfulness-based intervention

Cannabis Use Disorder (CUD) affects 22 million people globally and can lead to adverse psychosocial outcomes, including failed attempts to cut down/quit despite the experience of mental health and cognitive problems. Such problems have been (partly) ascribed to neurobiological alterations within pathways of the addiction neurocircuitry and high in cannabinoid receptors type 1 (CB1R), to which delta-9-tetrahydrocannabinol binds to exert its psychoactive effects. Emerging functional neuroimaging (fMRI) evidence show that cannabis users vs controls showed altered brain function while resting (i.e., without performing cognitively demanding tasks), measured via resting-state functional connectivity (rsFC); the evidence has not been synthesised systematically.

Study 1 is a PROSPERO pre-registered systematic literature review of 21 studies examining rsFC differences between 737 cannabis users and 659 controls, and their associations with metrics of cannabis exposure and related problems. Cannabis users vs controls showed altered rsFC in fronto-frontal, frontostriatal, and fronto-temporal region pairings, and selected brain pathways correlated with cannabis exposure metrics. Methodological limitations precluded a detailed understanding of the nature of rsFC alterations. For example, it was unclear if rsFC changes were driven by dependent use/CUD, because no study had measured if cannabis users endorsed a CUD using current diagnostic tools (i.e., DSM-5). Furthermore, if rsFC alterations are specific to cannabis use was unclear due to inconsistent accounting for key demographics and substance use/mental health confounders entrenched with cannabis use known to affect brain function. Finally, the behavioural significance of rsFC alterations remained unclear, as it has seldom been examined in relation to cannabis exposure and related problems.

Study 2 aimed to address the limitations of the literature, via examining 107 people aged 18-56 years (35 female) via fMRI scanning, socio-demographic, substance use, mental health, and cognitive testing. The primary aim was to compare rsFC between 65 individuals with a moderate-to-severe CUD who had tried to cut down or quit, and 42 controls, controlling for age, sex, alcohol and nicotine exposure, and depression symptom scores. Regions implicated in addiction neurocircuitry, dense in CB1R, and implicated in cognitive processes altered in cannabis users were selected as regions-of-interest (ROIs). Associations between CUD group rsFC changes and metrics of cannabis exposure and related problems were explored. People with a CUD vs controls showed greater rsFC between the following region pairings: nucleus accumbens (NAc)-frontal; pallidum-occipital/occipito-parietal, in correlation with CUD severity and cannabis use days/month; and putamen-occipito-parietal, in correlation with an earlier age of cannabis use onset; and lower hippocampus-occipital rsFC. Thus far, it is unclear if altered rsFC in CUD can be mitigated using psychological interventions.

Study 3 examined if altered rsFC shown in the CUD group in Study 2 (n=56, aged 18-51 years), could be mitigated using one of the following ~2-week interventions: a mindfulness-based intervention (MBI, n=19), active placebo (relaxation; n=18), and passive placebo (daily monitoring; n=19). It used a double-blind, pseudo-randomised design based on age and sex. The primary aim was to examine intervention-group-by-time effects on rsFC in a priori ROIs with altered rsFC identified in Study 2 (i.e., NAc, putamen, pallidum, hippocampus), and how changes in rsFC correlated with those in cannabis exposure and related variables. Pre-to-post MBI, putamen-superior frontal gyrus (SFG)/frontal pole rsFC decreased; and hippocampus-anterior cingulate rsFC increased (correlated with more cannabis use days). Pre-to-post active placebo, putamen-frontal pole rsFC increased, correlated with decreased cannabis grams; putamen-SFG/cerebellum/brainstem rsFC increased; and pallidum-anterior superior temporal gyrus (aSTG) rsFC decreased. Pre-to-post passive placebo, putamen-frontal pole rsFC increased, correlated with less cannabis use days; pallidum-aSTG rsFC increased; and hippocampus-anterior cingulate and putamen-SFG/cerebellum/brainstem rsFC decreased.

Findings from the thesis demonstrated rsFC alterations in cannabis users and confirmed existence of such alterations in CUD, and that alterations can be mitigated with a brief MBI, as well as relaxation and daily monitoring. rsFC alterations may reflect cannabis exposure or related problem (or both), or a neurobiological vulnerability predating the onset of cannabis use/CUD. Future fMRI studies with larger samples are required to confirm findings and to track over time if continuation of MBI, active and passive placebo interventions consolidate the effects reported herein. The results from this thesis expand upon neuroscientific theories of addiction validated in substances other than cannabis, by confirming partially overlapping alterations in CUD, and by showing that brief psychological interventions can target brain dysfunction in CUD.