The Relationship Between Cannabis, Cognition, and Schizophrenia: It's Complicated.

The consequences of cannabis use, especially in the context of schizophrenia, have gained increased importance with the legalization of cannabis in North America and across the globe. Cannabis use has multifaceted impacts on cognition in schizophrenia patients and healthy subjects. Healthy subjects, particularly those who initiated cannabis use at earlier ages and used high-potency cannabis for longer durations, exhibited poorer cognition mainly in working memory and attention. Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes. However, cannabis-using patients have better overall cognitive performance compared to patients who were not cannabis users. Interestingly, these effects were only apparent in lifetime cannabis users, but not in current (or within last 6 months) users. Moreover, higher frequency and earlier age of cannabis use initiation (i.e., before 17 years of age) were associated with better cognitive performance, although they had an earlier illness onset. Three possible hypotheses seem to come forward to explain this paradox. First, some components of cannabis may have antipsychotic or cognitive-enhancing properties. Secondly, chronic cannabis use may alter endocannabinoid signaling in the brain which could be a protective factor for developing psychosis or cognitive impairments. A third explanation could be their representation of a phenotypically distinct patient group with more intact cognitive functioning and less neurodevelopmental pathology. Multiple factors need to be considered to understand the complex relationship between cannabis, cognitive function, and schizophrenia. In short, age at initiation, duration and rate of cannabis use, abstinence duration, co-use of substances and alcohol, prescribed medications, relative cannabinoid composition and potency of cannabis, presence of genetic and environmental vulnerability factors are prominent contributors to the variability in outcomes. Animal studies support the disruptive effects of Δ9-tetrahydrocannabinol (THC) administration during adolescence on attention and memory performance. They provide insights about interaction of cannabinoid receptors with other neurotransmitter systems, such as GABA and glutamate, and other regulatory molecules, such as PSD95 and synaptophysin. Cannabidiol (CBD), on the other hand, can improve cognitive deficits seen in neurodevelopmental and chemically-induced animal models of schizophrenia. Future studies focusing on bridging the translational gaps between human and animal studies, through the use of translationally relevant methods of exposure (e.g., vaping), consistent behavioral assessments, and congruent circuit interrogations (e.g., imaging) will help to further clarify this complex picture.