Marijuana Use Disorder, Subcortical Dopamine Hyper-Connectivity and Psychosis—Is There a Connection?

A continued effort to legalize the unrestricted access and use of marijuana in the U.S., primarily through voter initiatives, continues in spite of clinical trial evidence of lack of efficacy, increasing teen use, and reports of serious consequences from accidents to mental illness.

As marijuana is currently viewed by the public as “safe until proven dangerous” rather than dangerous until proven safe and effective, by way of randomized double blind clinical trials for a specific medical problem, we cannot make any claims regarding its medical benefit.

Risk of Psychosis

Little is known about the long-term effects of marijuana use as concern rises regarding the impact on the developing brains of young initiates. The effect of the psychoactive ingredient in cannabis, Δ9- tetrahydrocannabinol (THC) on subcortical neuronal connectivity and function is the most recent concern as increased prevalence of psychiatric morbidity have been reported in the medical literature— including depression, suicidality, panic, paranoia, amotivation, increased risk for psychosis and now, a six-fold increase in the risk of schizophrenia among the youngest initiates.

These deleterious outcomes have been reported for those using easily attainable, high potency cannabis products. The aforementioned risk factors remain after controlling for confounding variables. Why or where or how persistent use produces these effects, and who might be the most vulnerable are under study, but the answers may be too late for children and teens who are already abusing marijuana. The functional organization of the brain’s subcortical regions that are modulated by dopamine (DA) is associated with psychiatric disease but the genetic contribution and mechanism by which psychiatric symptoms emerge is not well-understood.

The authors of this important research suggest that individuals with marijuana use disorder are more likely to have genetically derived variants that result in abnormalities in striatal DA, including transcription errors in the Dopamine Receptor Dopamine 2 (DRD2) alleles. These individuals are at greater risk for various psychiatric morbidities, including psychosis, when compared with marijuana abusing persons without these genetic variants. Accordingly, the authors suggest that regular marijuana use is associated with altered resting-state functional connectivity in the midbrain and striatal DA circuitry.

This novel research consisted of assessing resting-state activity of the subcortical brain regions in 441 young adults from the Human Connectome Project, including 30 marijuana addicted subjects and 30 matched controls.

As hypothesized, localized functional connectivity density was most prominent in the amygdala, hippocampus, ventral striatum, dorsal midbrain, and posterior-ventral brainstem. Among marijuana addicted subjects, increased hubs of functional DA connectivity density were observed, relative to control subjects. These hubs were discovered in nuclei associated with DA activity including the ventral striatum where the nucleus accumbens is located, the midbrain where substantia nigra and ventral tegmental nuclei, where both peripheral and central DA are produced respectively, but also in the brainstem and lateral thalamus. These effects were observed in the absence of significant differences in subcortical DA volumes and were most pronounced among individuals who initiated marijuana use during early adolescence and were associated with elevated negative emotional states.

Why Does This Matter?

Although there is much to learn regarding the role of marijuana use and concurrent psychopathology, these findings support the hypothesis that prevention and early intervention for children and adolescents, young adults, and pregnant females is essential and a highly worthy goal. Bottom line is clear. Early onset and persistent, long-term marijuana use is associated with changes in resting-state brain function in the same dopaminergic nuclei and regions associated with brain reward, habit formulation and psychiatric illness, including psychosis.

Peter Manza, Dardo Tomasi, and Nora D. Volkow. Subcortical Local Functional Hyperconnectivity in Cannabis Dependence. Biological Psychiatry, 2018 (In Press)