Examining the Relationship between Cannabis Use and Psychotic Disorders

Cannabis use has become increasingly prevalent, driven by changing laws and increasing potency. While its medicinal benefits in treating conditions such as epilepsy, multiple sclerosis, and chronic pain are well-documented, its potential role as a trigger or exacerbating factor for psychotic disorders is a subject of ongoing research. This rising trend has ignited a significant debate about its long-term health impacts, particularly concerning psychosis. Despite growing evidence suggesting an association between cannabis use and psychotic disorders, the question of causality remains contentious.

The correlation between cannabis use and psychotic disorders

Recent epidemiological studies have highlighted a potential link between cannabis use and an increased prevalence of psychotic disorders. A notable study reported a 2.5-fold increase in self-reported psychosis in the U.S. between 2001–2002 and 2012–2013. This study used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), comparing reports of psychosis diagnosed by healthcare professionals across two periods.

Findings showed that individuals with any cannabis use or cannabis use disorder were at a heightened risk of psychosis, and this risk appeared to be increasing over time. This data aligns with similar international findings, such as those from Denmark, which also observed a rising incidence of schizophrenia and related disorders alongside increased cannabis use.

Cannabis use and psychotic disorders in individuals with a family history of psychosis

While cannabis is often perceived as a relatively benign substance, increasing evidence suggests that it can pose significant risks to individuals with a personal or family history of psychosis. Studies have indicated that individuals who use cannabis, especially from a young age, are at a higher risk of developing psychosis later in life. This risk is significantly magnified in individuals with a genetic predisposition to mental health disorders. Included in this group are those with a family history of psychosis.

A recent study examined the clinical correlation between cannabis use, family history of mental illness, and the onset and progression of psychosis. This study revealed that a significant proportion of adolescents with first-episode psychosis (FEP) had a history of cannabis use. Among the adolescents with a family history of mental illness, 66.7% also reported cannabis use. This association highlights the potential for cannabis to exacerbate underlying genetic vulnerabilities. It may increase the risk of psychosis in individuals with a family history of mental health disorders.

Genetic factors that may explain the correlation between cannabis use and psychotic disorders

Experimental studies support the association by demonstrating that THC, the psychoactive component of cannabis, can induce symptoms akin to schizophrenia in some individuals. However, genetic research complicates the picture. Genetically informed methods suggest that while there may be a bidirectional relationship between cannabis use and schizophrenia, genetic predispositions could play a significant role in this interplay.

Mendelian randomization studies further explore this using genetic variants to infer causal relationships. Findings indicate that while cannabis use disorder might increase schizophrenia risk, genetic factors may contribute to this risk independently of cannabis exposure.

Notably, not all individuals who consume cannabis develop psychosis. This suggests that genetic factors may influence susceptibility. Several studies have explained the genetic polymorphisms associated with cannabis-induced psychosis. These focus on the dopaminergic system and other relevant genes. Below are quick insights from studies that may help in understanding the correlation between cannabis use and psychotic disorders.

The dopaminergic system and its genetic modulators

The dopaminergic system is critical in regulating mood, cognition, and perception. Dysregulation in this system is strongly associated with psychotic disorders, particularly schizophrenia. Several studies have identified specific genes within this system that may contribute to the psychosis-inducing effects of cannabis.

Catechol-O-Methyltransferase (COMT) Gene. The COMT gene encodes an enzyme involved in the breakdown of dopamine, particularly in the prefrontal cortex. A well-studied polymorphism in this gene, rs4680, results in valine (Val) substitution for methionine (Met), which affects the enzyme’s activity. The Val allele is associated with higher enzymatic activity. This leads to increased dopamine catabolism and lower extracellular dopamine levels. Several studies have linked the Val allele to a heightened risk of cannabis-induced psychosis. For instance, carriers of the Val allele have shown a greater likelihood of developing psychotic symptoms after cannabis use, an earlier onset of these symptoms, and a more robust response to THC-induced psychosis.

AKT1 Gene. The AKT1 gene is another significant player in the dopaminergic pathway. Polymorphisms in this gene, particularly rs2494732, have been associated with an increased risk of psychosis in cannabis users. Studies have shown that individuals with the C/C genotype at this locus are more likely to develop a psychotic disorder when using cannabis. This association has been observed in multiple studies, suggesting a robust link between AKT1 and cannabis-induced psychosis. The gene’s role in dopamine signaling further supports its relevance.

Additional genetic modulators

DRD2 Gene. The DRD2 gene encodes the D2 subtype of the dopamine receptor, which is a critical target in treating psychotic disorders. A functional polymorphism in this gene, rs1076560, has been shown to modulate the risk of psychosis in cannabis users. Specifically, carriers of the T allele have a threefold increased risk of developing a psychotic disorder after cannabis use. This finding highlights the importance of dopamine receptor signaling in mediating the psychotic effects of cannabis.

Dopamine Transporter (DAT1) Gene. The DAT1 gene encodes the dopamine transporter responsible for the reuptake of dopamine from the synapse. A variable number tandem repeat (VNTR) polymorphism in the 3′ UTR of this gene has been shown to affect DAT1 expression. Carriers of the 9-repeat allele of this polymorphism exhibit increased sensitivity to the psychotic effects of THC, as demonstrated in a study involving healthy volunteers. This suggests that variations in dopamine transport can influence an individual’s response to cannabis, potentially increasing the risk of psychosis.

Other genetic factors beyond the dopaminergic system

While much of the research has focused on the dopaminergic system, other genes have also been implicated in the relationship between cannabis use and psychosis.

Brain-derived neurotrophic Factor (BDNF) Gene. BDNF is crucial in developing and maintaining the central nervous system, influencing serotonergic signaling and neuronal growth. Researchers have investigated rs6265 polymorphism in the BDNF gene, which results in a Val66Met substitution, for its potential role in cannabis-induced psychosis. However, studies have not found a significant association between this polymorphism and the age of onset of psychosis in cannabis users, suggesting that BDNF may not be a substantial factor in this context.

Cholinergic Receptor Muscarinic 3 (CHRM3) Gene. The CHRM3 gene, which encodes a muscarinic receptor involved in cholinergic signaling, is linked to cannabis-induced hallucinations (Ca-HL). A genome-wide association study (GWAS) identified a significant association between this gene and Ca-HL in European Americans, with nominal replication in African Americans. Animal studies support the idea that CHRM3 plays an inhibitory role in dopamine release, with its disruption potentially leading to psychosis. This finding suggests that cholinergic signaling may also contribute to the psychotic effects of cannabis.

Additional genetic factors

Purinergic Receptor P2X7 (P2RX7) Gene. The P2RX7 gene, which encodes a receptor involved in purinergic signaling, has been implicated in psychotic-like experiences (PLE) in regular cannabis users. An SNP in this gene, rs7958311, has been associated with an increased risk of PLE, particularly in individuals with high levels of cannabis use. This suggests that purinergic signaling may play a role in the neurobiological mechanisms underlying cannabis-induced psychosis.

Fatty Acid Amide Hydrolase (FAAH) Gene. The FAAH gene encodes an enzyme involved in the breakdown of endocannabinoids, which are natural ligands for the cannabinoid receptors targeted by THC. A polymorphism in this gene, rs324420, has been studied for its potential role in cannabis-induced psychosis. However, recent research has not found a significant association between this variant and psychotic-like or euphoric experiences induced by cannabis. Despite this, the involvement of the endocannabinoid system in psychosis remains a critical area of research, particularly given the role of cannabinoids in modulating neurotransmitter release.

Challenges and future directions in cannabis research

The studies reviewed here highlight the complex interplay between genetic factors and cannabis use in the development of psychotic disorders. However, several challenges remain in interpreting these findings. One major issue is the heterogeneity in study designs, phenotypes, and outcome measures. This makes it difficult to draw definitive conclusions. Additionally, the relatively small sample sizes in many studies limit the generalizability of the results.

Future research should focus on larger, more comprehensive studies, such as genome-wide association studies (GWAS) and polygenic risk score (PRS) analyses, to overcome these challenges. These approaches can help identify novel genetic targets and provide a more holistic understanding of the genetic factors involved in cannabis-induced psychosis. Moreover, the integration of genetic data with environmental factors, such as cannabis use patterns, through genome-wide environment interaction studies (GWEIS) and exposome studies may offer new insights into the gene-environment interactions that contribute to psychosis.