Peripheral endocannabinoids in major depressive disorder and alcohol use disorder: a systematic review.

BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are two high-prevalent conditions where the Endocannabinoid system (ECS) is believed to play an important role. The ECS regulates how different neurotransmitters interact in both disorders, which is crucial for controlling emotions and responses to stress and reward stimuli. Measuring peripheral endocannabinoids (eCBs) in human serum and plasma can help overcome the limitations of detecting endocannabinoid levels in the brain. This systematic review aims to identify levels of peripheral eCBs in patients with MDD and/or AUD and find eCBs to use as diagnostic, prognostic biomarkers, and potential therapeutic targets. METHODS: We conducted a systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines from the earliest manuscript until October 22, 2023, in three electronic databases. We included studies of human adults who had a current diagnosis of AUD and/or MDD and evaluated plasma or serum endocannabinoids. We carefully considered known variables that may affect endocannabinoid levels. RESULTS: We included 17 articles in this systematic review, which measured peripheral eCBs in 170 AUD and 359 MDD patients. Stressors increase peripheral 2-arachidonyl-glycerol (2-AG) concentrations, and 2-AG may be a particular feature of depression severity and chronicity. Anxiety symptoms are negatively correlated with anandamide (AEA) concentrations, and AEA significantly increases during early abstinence in AUD. Studies suggest a negative correlation between Oleoylethanolamide (OEA) and length of abstinence in AUD patients. They also show a significant negative correlation between peripheral levels of AEA and OEA and fatty acid amide hydrolase (FAAH) activity. Eicosapentaenoylethanolamide (EPEA) is correlated to clinical remission rates in depression. Included studies show known variables such as gender, chronicity, symptom severity, comorbid psychiatric symptoms, length of abstinence in the case of AUD, and stress-inducibility that can affect peripheral eCBs. CONCLUSIONS: This systematic review highlights the important role that the ECS plays in MDD and AUD. Peripheral eCBs appear to be useful biomarkers for these disorders, and further research may identify potential therapeutic targets. Using accessible biological samples such as blood in well-designed clinical studies is crucial to develop novel therapies for these disorders.

CANreduce-SP-adding psychological support to web-based adherence-focused guided self-help for cannabis users: study protocol for a three-arm randomized control trial.

BACKGROUND: Cannabis is the most-frequently used illicit drug in Europe. Over the last few years in Spain, treatment demand has increased, yet most cannabis users do not seek treatment despite the related problems. A web-based self-help tool, like CANreduce 2.0, could help these users to control their consumption. METHODS: This study protocol describes a three-arm randomized controlled trial (RCT) comparing the effectiveness of three approaches, in terms of reducing cannabis use among problematic cannabis users, the first two treatment arms including the Spanish version of CANreduce 2.0 (an adherence-focused, guidance-enhanced, web-based self-help tool) (1) with and (2) without psychological support; and the third group (3) treatment as usual (TAU). Study hypotheses will be tested concerning the primary outcome: change in the number of days of cannabis use over the previous week, comparing assessments at 6 weeks and 3 and 6 months follow-up between groups and against baseline. Secondary outcomes related to cannabis use will be tested similarly. Mental disorders will be explored as predictors of adherence and outcomes. Analyses will be performed on an intention-to-treat basis, then verified by complete case analyses. DISCUSSION: This study will test how effective the Spanish version of CANreduce 2.0 (CANreduce-SP) is at reducing both the frequency and quantity of cannabis use in problematic users and whether adding psychological support increases its effectiveness. TRIAL REGISTRATION: This trial is registered with the Clinical Trials Protocol Registration and Results System (PRS) number: NCT04517474 . Registered 18 August 2020, (Archived by archive.is https://archive.is/N1Y64 ). The project commenced in November 2020 and recruitment is anticipated to end by November 2022.