A team led by a two-time BBRF grantee has published research suggesting the possibility that cannabis use in some individuals may be associated with a distinct subtype of first-episode psychosis (FEP).

Deepak Cyril D’Souza, M.B.B.S., M.D., a professor of psychiatry at Yale University, director of the Schizophrenia Neuropharmacology Research Group at Yale, and a clinician and researcher in the VA Connecticut Healthcare System, headed a study of male patients recently admitted to hospital with a first episode of psychosis, who were then observed during 4 weeks of inpatient treatment. 66 had confirmed cannabis exposure and 53 had no exposure to cannabis. They were treated at the Central Institute of Psychiatry, in Ranchi, India.

Dr. D’Souza is a 2013 BBRF Independent Investigator and 1993 Young Investigator. The team also included Jose Cortes-Briones, Ph.D., a 2015 BBRF Young Investigator, who was co-first author of the team’s paper; and Suhas Ganesh, M.B.B.S., M.D., a 2018 BBRF Young Investigator. The study appeared in The American Journal of Psychiatry.

Those FEP patients in the study with cannabis exposure are described as having “cannabis-associated psychosis.” Importantly, this designation does not indicate that cannabis use was necessarily the cause of the psychotic episode. Cannabis-induced psychosis is an acute state thought to be triggered directly by cannabis use. Cannabis-associated psychosis is a broader term covering cases where cannabis is used by someone with a primary psychotic disorder, where causality cannot be determined definitively.

Whether or not cannabis use is deemed a direct cause or a risk factor for psychotic disorders, including a first episode of psychosis, the relationship between the drug and psychosis is an important subject of research, and one, according to Dr. D’Souza and colleagues, that is increasingly important. "The incidence of cannabis[-related] psychosis has increased in parallel with the increasing potency of cannabis,” as well as increased availability of the drug following widespread legalization. At the same time, “converging lines of evidence suggest exposure to cannabis and synthetic cannabinoids may contribute to the risk of psychosis, ranging from short-lived psychotic states to longer-lasting psychoses that require clinical intervention,” they note.

According to research conducted in Scandinavia, “up to 50% of patients with an episode of cannabis-induced psychosis [were] later diagnosed with schizophrenia or bipolar disorder,” the team notes. This is particularly true of men in this group, up to half of whom were diagnosed with schizophrenia within 2 years of cannabis-induced psychosis. This evidence, they say, raises the possibility that cannabis-induced psychosis in men “may be a harbinger of chronic, recurrent psychotic disorder” that under current diagnostic norms is classified as schizophrenia.

Yet the research literature characterizing cannabis-related psychosis is thin and suffers from various limitations, the team says. Past studies have relied on self-reports of cannabis exposure without toxicology testing and have not adequately controlled for the use of other drugs or preexisting psychosis.

With these issues in mind the team carefully examined the 119 men analyzed in their new study, most of whom were in their mid-to-late 20s. Apart from nicotine, none used other drugs; those using cannabis prior to their psychotic episode had been using the drug for 8 years, on average. All had their cannabis status confirmed in lab tests and interviews with family members. In addition to making behavioral comparisons of the cannabis-associated and non-cannabis subgroups with a first psychotic episode, the team also assessed cognition, as well as brain activity via electroencephalography (EEG). Assessments were made within 3 days of hospital admission and again after 4 weeks of conventional treatment for hospitalized FEP patients.

Although there were no notable differences in cognitive performance between the two groups upon admission to the hospital, test performance significantly improved in the cannabis-exposed group but not in the unexposed group after a month of treatment.

The “positive symptoms” of psychosis (e.g., hallucinations, delusions disorganized thinking) were similar in the two groups upon admission for FEP, but cannabis-exposed individuals had significantly lower scores for “negative symptoms” (e.g., blunted affect, anhedonia, asociality) and total psychosis symptoms. The cannabis-exposed participants had more depressive and manic symptoms. Both groups responded similarly to treatment.

Notably, of 16 cannabis-exposed study participants who were tracked post-discharge, 10 were re-hospitalized for a relapse of psychosis due to resumption (following the study) of cannabis use. The researchers say this provides support for a causal link between cannabis use and psychosis relapse, although data from many more patients will be needed to flesh out such a hypothesis.

EEG data, which reflects neural activity at various frequencies in the brain, suggested that the cannabis-exposed patients had a distinct and lower cortical “E/I balance” (i.e., a reduction in the ratio of excitatory to inhibitory neural activity). E/I balance, broadly, refers to the ever-changing balance between excitation and inhibition in the brain. FEP patients who had not been exposed to cannabis showed greater cortical disinhibition, another factor which may distinguish FEP and perhaps also psychosis in cannabis-exposed and -unexposed individuals, the team said.

The researchers suggested that exposure to cannabis, especially during adolescence, may have an important impact on several processes impacting E/I balance. It is during the adolescent years, they noted, that the prefrontal cortex undergoes functional remodeling, which includes refinement of the function of inhibitory circuitry and consequent modifications in E/I balance.

Related to this process, the body’s naturally occurring endocannabinoid system plays an important role, for example in the pruning of synaptic connections between neurons, a key event in the maturation of neural circuits. Importantly, the body’s endocannabinoids “are produced on demand, are actively removed or inactivated, and have very local effects,” the team noted. In contrast, THC from cannabis “floods the brain,” activating endocannabinoid receptors “indiscriminately, and for longer period of time.” This, they speculate, may disrupt normal endocannabinoid receptor-mediated developmental processes and the maturation of inhibitory neurons in the prefrontal cortex, “potentially leading to long-term dysfunction in prefrontal E/I balance and desynchronization of prefrontal cortex neuronal networks.”

Taken together, the results of this study suggested to the investigators that “first-episode cannabis-related psychosis differs from psychosis unrelated to cannabis in its cognitive, electrophysiological, and behavioral profile.” Because cannabis use and potency are on the rise, and because cannabis-associated psychosis cases continue to increase in number, the team urges further research to replicate its findings “and determine if psychosis related to cannabis has a distinct course, response to existing treatments, and prognosis.”