Psychosis associated with cannabis withdrawal: systematic review

Chesney, E., Reilly, T. J., Scott, F., Slimani, I., Sarma, A., Kornblum, D., … & McGuire, P. (2024). Psychosis associated with cannabis withdrawal: systematic review and case series. The British Journal of Psychiatry, 1-12.

Rationale

The research was conducted to address the growing concern regarding the potential link between cannabis withdrawal and the onset or relapse of psychosis.

While previous research has established a connection between cannabis use and psychosis, the specific impact of withdrawal had been less explored.

Studies like Schäfer and colleagues (2019) and Paparelli and colleagues (2011) indicated a correlation between cannabis use and the clinical course of psychosis, but the unique contribution of withdrawal remained unclear.

This systematic review and meta-analysis aimed to fill this gap by comprehensively analyzing existing literature and clinical data to provide a clearer understanding of the association between cannabis withdrawal and psychosis.  

Method

Systematic Review

• PRISMA Adherence: The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring transparency and methodological rigor.  
• Databases and Time Frame: The search encompassed PsycINFO, Embase, and MEDLINE databases from their inception dates up to June 12, 2024.  
• Search Terms: Keywords used included: (cannabis OR marijuana OR marihuana OR tetrahydrocannabinol OR THC OR cannabinoid*) AND (psychosis OR psychotic OR schizophrenia OR schizophreniform OR schizoaffective OR mania OR bipolar OR hallucinat* OR delusio* OR paranoi*) AND (withdrawal OR discontinuation OR cessation).  
• Inclusion/Exclusion Criteria: Studies were included if they described psychosis or mania triggered by cannabis withdrawal, encompassing case reports, case series, controlled trials, and other relevant research designs.  
• Final Study Count: The systematic review included 21 studies, comprising 44 individual cases where cannabis withdrawal preceded acute psychosis.  
• Data Extraction: Two authors independently extracted data, including demographics, psychiatric history, substance use patterns, and details of the psychosis episodes, with discrepancies resolved by a third author.  

Health Record Analysis

• Data Source: The South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register, containing over 400,000 patient records, was searched using the Clinical Record Interactive Search (CRIS) system.  
• Search Strategy: The search used terms related to cannabis withdrawal and psychosis, including diagnostic codes and free-text clinical entries.  
• Inclusion/Exclusion Criteria: Cases were included if two psychiatrists agreed that the patient experienced a psychotic episode ‘probably’ or ‘definitely’ associated with cannabis withdrawal, lasting at least seven days.  
• Data Extraction: Researchers reviewed clinical records to extract demographic data, cannabis use history, withdrawal symptoms, psychotic symptoms (using the Operational Criteria in Studies of Psychotic Illness, OPCRIT), clinical management, and relapse information.  

Statistical Measures

Health Record Analysis

• Descriptive Statistics: Continuous variables were reported as means with standard deviations or medians with interquartile ranges, while categorical variables were presented as frequencies.  
• Correlation Analysis: Spearman’s rank correlation was used to analyze the relationship between the number of cases and the year of presentation.  
• Chi-Squared Test: The association between psychosis relapse and cannabis use trajectory (abstinence versus continued use) was analyzed using a Chi-squared test.  
• Significance Level: The threshold for statistical significance was set at P < 0.05.  
• Inter-rater Reliability: Cohen’s kappa was used to assess the reliability of OPCRIT data extraction between psychiatrists.  

Results

Systematic Review

• Identified Cases: The systematic review identified 44 individuals from 21 studies who experienced acute psychosis following cannabis withdrawal.  
• Demographics and Clinical Features: Most cases were male (85.3%) with a mean age of 26.2 years. The majority were heavy cannabis users who abruptly stopped using, with a median time of 6 days from cessation to psychosis onset. Common symptoms included sleep disturbance, irritability, anxiety, delusions, and hallucinations. Almost all required antipsychotic medication and inpatient admission.  

Health Record Analysis

• Identified Cases: The health record search yielded 68 individuals with cannabis withdrawal-associated psychosis, including 47 first-episode cases and 21 relapses.  
• Demographics: The sample was predominantly male (82.4%) with a mean age of 27.3 years.  
• Cannabis Use: Most were daily users (86.8%) who primarily used high-potency cannabis and abruptly stopped (80.9%).  
• Withdrawal Symptoms: Common symptoms included sleep difficulty (89.7%), restlessness (72.1%), reduced appetite (69.1%), and hostility (64.7%).  
• Psychosis Symptoms: The most prevalent psychotic symptoms were persecutory delusions (76.5%), poor appetite (70.6%), insomnia (69.1%), loss of insight (69.1%), and agitated activity (67.6%).  
• Clinical Management: The majority required hospital admission (75%) and antipsychotic medication (89.7%).  
• Relapse: Individuals who continued cannabis use after the psychotic episode had a significantly higher risk of relapse compared to those who abstained (odds ratio 13.9).  

Insight

This study provides compelling evidence for the emergence of acute psychosis following cannabis withdrawal, a phenomenon observed in both first-episode psychosis and relapses of pre-existing psychotic disorders.

The findings are particularly significant given the increasing prevalence of cannabis use, especially high-potency strains, and the trend toward legalization in various regions.

The high proportion of cases experiencing severe sleep disturbances prior to psychosis onset highlights a potential mechanism linking withdrawal to psychotic symptoms.

This suggests that addressing sleep problems during withdrawal could be a crucial intervention strategy.  

Compared to previous research focusing primarily on cannabis use and psychosis, this study specifically isolates the impact of withdrawal, offering a more nuanced understanding of the relationship.

The findings emphasize the need for increased awareness among clinicians regarding cannabis withdrawal-associated psychosis, enabling early identification and targeted interventions.  

Future research could explore the neurobiological mechanisms underlying this phenomenon, particularly the role of dopamine and other neurotransmitter systems in the transition to psychosis during withdrawal.

Additionally, investigating the impact of different cannabis strains, potencies, and patterns of use on withdrawal-related psychosis could inform personalized prevention and treatment strategies.  

Clinical Implications

The study’s findings have significant implications for healthcare practitioners and policymakers.

Clinicians should be vigilant about the potential for psychosis to emerge during cannabis withdrawal, especially in heavy users.

Incorporating routine screening for cannabis use and withdrawal symptoms into mental health assessments can facilitate early identification and intervention.  

Developing targeted interventions to manage withdrawal symptoms, particularly sleep disturbances, could potentially mitigate the risk of psychosis.

Educating patients about the potential for withdrawal-related psychosis is crucial, empowering them to make informed decisions about their cannabis use and seek timely support if needed.  

For policymakers, these findings underscore the importance of considering the potential mental health consequences of cannabis legalization and implementing public health measures to minimize risks.

This includes regulating cannabis potency, providing clear information about potential harms, and ensuring access to evidence-based treatment for cannabis use disorders and psychosis.  

Implementing these findings into clinical practice may be challenging due to limited resources, stigma surrounding cannabis use, and the complexity of managing psychosis.

However, the potential benefits in reducing the incidence and severity of psychosis associated with cannabis withdrawal make these efforts crucial.  

Strengths

• Comprehensive Systematic Review: The study conducted a thorough systematic review, adhering to PRISMA guidelines, ensuring a robust and transparent methodology.  
• Large Sample Size: The analysis of a large dataset of health records provided a substantial sample size, increasing the statistical power and generalizability of the findings.  
• Real-World Setting: The use of electronic health records allowed for the examination of cannabis withdrawal-associated psychosis in a real-world clinical setting, enhancing the ecological validity of the study.  
• Detailed Data Extraction: The researchers extracted comprehensive data on demographics, cannabis use patterns, withdrawal symptoms, and psychotic experiences, providing a rich and nuanced understanding of the phenomenon.  
• Inter-rater Reliability: The high inter-rater reliability for OPCRIT data extraction ensured the consistency and accuracy of the assessment of psychotic symptoms.  

Limitations

• Retrospective Design: The health record analysis was retrospective in nature, relying on previously recorded clinical data, which may be subject to inconsistencies or missing information.  
• Under-Recognition of Withdrawal: The study found that cannabis withdrawal was often not documented in the health records, suggesting potential underestimation of the prevalence of withdrawal-associated psychosis.  
• Limited Information on Cannabis Use: The variability in the quality and quantity of data regarding cannabis use patterns, such as potency and frequency, may limit the precision of the analysis.  
• Potential Confounding Factors: The study did not fully control for potential confounding factors, such as comorbid substance use or other environmental factors, which may contribute to the development of psychosis.  
• Generalizability: The sample was predominantly male and from a specific geographical region, which may limit the generalizability of the findings to other populations.  

References

Chesney, E., Reilly, T. J., Scott, F., Slimani, I., Sarma, A., Kornblum, D., … & McGuire, P. (2024). Psychosis associated with cannabis withdrawal: systematic review and case series. The British Journal of Psychiatry, 1-12.

Barkus, E., Morrison, P. D., Vuletic, D., Dickson, J. C., Ell, P. J., Pilowsky, L. S.,… & McGuire, P. K. (2011). Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study. Journal of Psychopharmacology, 25(11), 1462–1468.

Schoeler, T., Petros, N., Di Forti, M., Klamerus, E., Foglia, E., Ajnakina, O.,… & Murray, R. M. (2016). Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study. Lancet Psychiatry, 3(10), 947–953.

Socratic Questions

• How might the retrospective nature of the health record analysis have influenced the findings of the study?
• What are the potential explanations for the under-recognition of cannabis withdrawal syndrome in clinical practice, and how might this be addressed?
• How could the findings of this study be used to inform the development of targeted interventions for individuals experiencing cannabis withdrawal?
• What are the ethical considerations surrounding the legalization of cannabis in light of the potential link between withdrawal and psychosis?
• How might the findings of this study be applied to different populations or contexts, such as adolescents or individuals with pre-existing mental health conditions?