Studies in both animals and humans have suggested that adolescence is a vulnerable time in which to begin using cannabis, owing to various ways it is thought to modify the brain’s development process. Of course, the adolescent years are precisely those in which young people so inclined will typically begin to experiment with cannabis or begin using it regularly.

But what exactly is its impact on the young brain? What are the potential consequences? A newly published study led by a recent BBRF grantee suggests how regular cannabis use may alter an important aspect of brain function in adolescents—the development and function of the dopamine neurotransmitter system, which plays a key role in reward processing and motivation.

As noted in their paper, appearing in Neuropsychopharmacology, the team, led by Sarah A. Thomas, Ph.D., a 2022 BBRF Young Investigator at Brown University and Bradley Hospital, the brain’s naturally occurring, or endogenous, cannabinoid system (sometimes called the endocannabinoid system) plays a role in supporting normal brain development. The question is what happens when exogenous cannabinoids—cannabis from plants or highly concentrated into vape or edible products—are added to the mix. There is no question that they perturb the function of the body’s own cannabinoid system, for example by competing for and potentially flooding cannabinoid receptors in the brain that are evolved to handle endocannabinoids.

The team’s research is relevant to the questions of whether regular cannabis use modifies the dopamine system, and whether such changes may be one factor associated with a greater risk of negative outcomes in young cannabis users. Most immediately, their work tests a method for detecting dopamine system changes in adolescents.

Evidence from animals and human adults indicates that cannabis use blunts dopamine neurophysiology. Synthesis of dopamine molecules is driven in part by an iron-dependent enzyme called tyrosine hydroxylase. Dopamine is stored in tiny balloon-like bodies called vesicles. In general, the rewarding effects of acute drug intoxication (not just cannabis) are attributed to increased levels of dopamine in the brain’s striatum; this dopamine comes from dopamine neurons in the ventral tegmental area (VTA), among other regions. In contrast, when a drug (including cannabis) is used habitually, dopamine-system activity has been noted to decrease. For example, in habitual users, there is reduced availability of dopamine receptors in the striatum.

What is known about the way cannabis affects the brain—including a link between chronic THC exposure and blunted dopamine synthesis—has been gleaned from studies in animals and human adults. Research on impacts in the adolescent brain has lagged, in part for methodological reasons, which explains the impetus behind the new study. Dopamine dynamics in adults are typically measured with PET imaging, but PET imaging is restricted for use in adolescent research, in part because it involves injecting a radioactive tracer, to which tissue in the developing brain is more sensitive than in adults.

There is, however, another way to proceed. It is based on the fact that tissue iron—iron stored in the body's cells—is an indirect proxy for activity in the dopamine system. Tissue iron “co-localizes” with vesicles containing dopamine molecules. It is most concentrated in the midbrain and basal ganglia (the latter are a collection of subcortical brain structures responsible for motor control, action selection, executive functions, and reward processing), and it can be measured indirectly via MRI brain scans, which can be performed in adolescents. Researchers know from past experiments that tissue iron levels in the basal ganglia normally increase with age during adolescent brain development, and follow the same developmental pattern from adolescence to adulthood as dopamine-related neurophysiology.

“Repeated cannabis use is believed to cause neurobiological adaptations over time that lead to problematic changes in behavior, cognition emotion, and cannabis use disorder,” the team noted. “Assessing dopamine-related neurophysiology is a crucial first step in evaluating the link between exogenous cannabis use and the developing adolescent brain.” Not only has dopamine-related physiology not yet been studied in relation to adolescent cannabis use; the team stresses that with the dramatic increase in cannabis potency in recent years, it is all the more important to study how cannabis may modify the dopamine system in young users. High-potency cannabis is already associated with faster progression to the first symptoms of cannabis use disorder (CUD) and a decline in overall mental health.

Using inferences of tissue iron based on MRI scans, the team performed a cross-sectional study which provides a snapshot of participants at a single moment in time. They collected information from each participant on the quantity of cannabis used, frequency, and CUD symptom severity, and then measured tissue iron levels in key subcortical regions with high dopamine activity. The cohort included 81 youths, ages 14-17. About two-thirds were female; 47 had fewer than 5 lifetime exposures to cannabis, while 34 had 11 exposures or more (many in this latter group later proved to be regular as opposed to occasional cannabis users). All participants in the study received a resting-state functional MRI brain scan, which was the basis for making inferences about dopamine-related neurophysiology. Participants had limited alcohol and nicotine use and none used illicit drugs.

In this first-ever study of the relationship between cannabis use and tissue iron-based inferences about the dopamine system, the team reported results “supporting the idea that repeated cannabis use is associated with reduced dopamine-related neurophysiology.” They noted that one important aspect of tissue iron levels “is their connection to the critical role of iron in dopamine synthesis, particularly in the storage of dopamine in presynaptic vesicles.”

This may help explain observations of lower dopamine-related physiology in adult cannabis users vs. controls: with repeated substance use, there may be fewer dopamine vesicles available for release due to loss of dopamine terminals—storage sites located at the end of axon branches from which dopamine is released during cell-to-cell communication.

In particular, the researchers saw that in adolescents, the VTA and the thalamus were frequently affected by cannabis-related changes in inferred dopamine neurophysiology. Both are “vital for reinforcement and goal-directed behaviors,” which may be perturbed with chronic drug use, they said. Lower dopamine-related signals in key striatal areas including the caudate and putamen, they added, “may indicate decreased motivation for non-drug rewards, potentially serving as a marker for future drug use risk as a compensatory response to dopamine deficits—a central mechanism in addiction development.” This, they said, was supported by their finding that the VTA had a significantly lower signal corresponding with decreased dopamine neurophysiology relative to the increasing severity of reported CUD symptoms in study participants.

Their findings also indicated a connection between cannabis potency and dopamine-related neurophysiology. The use of highly concentrated cannabis products had a stronger link to the reduced dopamine signal than either the quantity or frequency of use of conventional lower-THC plant-based cannabis (“flower”).

The team said their results are most applicable to adolescents with established, recurrent cannabis use rather than light or experimental use. While more research needs to be performed on the relation of dopamine and cannabis use, they said, their own results support the notion that estimating subcortical tissue iron may be “crucial for identifying the lasting effects of cannabis use during development, including initiating other drug use, emerging mental health symptoms, and increased risk of developing CUD.”