By Kate Johnson

The heavy, long-term use of cannabis is associated with negative changes in parts of the brain not previously implicated, and is linked to deficits in learning and memory, new research suggests.

"In light of a current trend toward legalizing marijuana, with potentially increased exposure of adolescents, we believe our findings are important to consider," said investigator Jodi Weinstein, MD, of the New York State Psychiatric Institute in New York City.

If used daily, cannabis "can be as bad as other drugs in terms of consequences," said senior investigator Anissa Abi-Dargham, MD.

"People often think of cannabis as a lighter, harmless drug. This study shows that it is not and that it has negative consequences,".

The team used the highly specific carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine radiotracer — known as [11C]PHNO — to image the impact of cannabis on the brain. The radiotracer binds preferentially to dopamine D₃ receptors. Because it is a different class of compound than most other D₂ and D₃ radiotracers — an agonist rather than an antagonist — it is sensitive to dopamine release.

With [11C]PHNO, the investigators showed that heavy chronic cannabis use is associated with lower dopamine release in the associative striatum and the sensory motor striatum, regions involved in cognition.

In contrast, previous reports have suggested that other drugs affect the limbic striatum, which processes reward information, Dr Weinstein explained.

"Cannabis shares a negative impact on dopaminergic transmission with other drugs, only with a different regional profile," explained Dr Abi-Dargham.

An exploratory analysis showed a significant association between lower dopamine release capacity in the associative striatum and decreased cognitive measures in probabilistic category learning and working memory tasks, Dr Weinstein reported.

In their study, the team compared 11 heavy cannabis users with 12 healthy control subjects, all approximately 28 years of age.

"Our average cannabis user started using in adolescence, at around 16 years, had been using for the previous 11 years, had been dependent before age 21, and in the previous month had been using almost every day," explained Dr Weinstein.

Cannabis users had no medical or psychiatric comorbidities and used no other drugs, including nicotine, she said.

After an inpatient abstinence period of 5 to 7 days, the study participants underwent a baseline PET scan with [11C]PHNO, followed by a second scan 3 hours after the oral administration of amphetamine.

Blunts Dopamine Release

Baseline scans did not differ significantly between the two groups, but dopamine release capacity was significantly different after amphetamine administration.

In the striatum as a whole, cannabis users had significantly less dopamine release than the control subjects (18.4% vs 24.9%; P = .002). Dopamine release was also significantly lower in the cannabis users than in the control subjects in the associative striatum (14.6% vs 21.1%; P = .003), the sensory motor striatal subregions (24.6% vs 32.3%; P = .003), and the pallidum (12.9% vs 22.6%; P = .012). However, there was no difference in dopamine release between the groups in the thalamus or midbrain.

"Our study provides definitive evidence that in heavy cannabis users, there is a detectable deficit of striatal dopamine release using an amphetamine challenge," said Dr Weinstein. "Within the striatum, the subdivisions seem to have a different pattern, in contrast to reports of other substance abuse. And our exploratory analysis suggests that the deficits we are seeing in dopamine release in the striatum have a functional significance — that lower dopamine release is associated with lower working memory and learning performance."

For schizophrenia, this study suggests "a potential mechanism by which cannabis may be contributing to the risk for psychosis or the severity of psychosis, specifically by interfering with dopamine transmission in one key brain region involved in psychosis — the head of the caudate," added Dr Abi-Dargham. "If this is repeatedly occurring at a young age, it could result in abnormal salience and could have offsite effects on the circuitry. These comments obviously are a little speculative, but can be further tested now that we have this information," she pointed out.

"This study is striking in that it provides further evidence that long-term cannabis use is associated with alteration in the function of key brain chemical messengers — in this case dopamine, a key chemical messenger for motivation and attention," said Oliver Howes, MD.

"The blunting of dopamine release that they find fits with other studies showing reduced dopamine synthesis in cannabis users. This could be linked to the addictive potential of cannabis and other problems, such as lack of motivation, seen in regular users," told Dr Howes.

Although "previous studies, including a study from the same group, did not show significant differences in striatal dopamine function between chronic cannabis users and controls, those studies used a more traditional tracer, raclopride, which binds to both dopamine D₂ and D₃ receptors," said Matthijs Bossong, PhD, from the Netherlands.

This study "used a specific dopamine D₃ receptor tracer, which suggests that striatal dopamine D₃ receptors are particularly involved in cannabis dependence," he explained. It also suggests that "[11C]PHNO may actually be a better tracer to measure acute dopamine fluctuations in the striatum. It has a better sensitivity."