Brain Cannabinoid CB1 Receptors Blunted in Cannabis Users

Nancy A. Melville

June 09, 2011

June 9, 2011 (San Antonio, Texas) — Chronic marijuana smokers show a decrease in cannabinoid CB1 receptor activity, which correlates with the number of years of cannabis smoking, but the deficits are reversed after just 4 weeks of abstinence, according to research presented here at the Society for Nuclear Medicine 2011 Annual Meeting.

Cannabinoid CB1 receptors influence brain functions, including pleasure, appetite, concentration, perception of time and memory, pain tolerance, and other psychological and physiological functions. Previous studies on rodents have shown a downregulation in CB1 receptors related to chronic cannabis exposure, followed by recovery during abstinence.

The receptors have come under focus since researchers at the National Institutes of Health developed a novel imaging agent to identify them in the human brain. The agent, a promising positron emission tomography (PET) ligand for the CB1 receptor — [18F]FMPEP-d2 ((3R,5R)-5-(3-(fluoromethoxy)phenyl)-3-((R)-1-phenylethylamino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one) — is a radioligand that combines a radioactive fluorine isotope and a neurotransmitter analog, and binds with CB1 brain receptors.

Brain scans showing CB1 receptor downregulation in the cortex of the human brain (red and yellow color)

In investigating whether similar patterns exist in humans, researchers used the new imaging agent to evaluate cannabinoid CB1 receptor patterns in chronic daily cannabis smokers and compare them with the brain scans of healthy male nonsmokers.

The study was a collaborative effort between the National Institute of Mental Health and National Institute on Drug Abuse, in Bethesda, Maryland.

The marijuana users (n = 30) had abused cannabis for an average of about 12 years, and were smoking about 10 joints per day before being enrolled in a closed inpatient research unit for approximately 4 weeks of abstinence.

They received PET scan brain imaging the day after admission and at the end of the 4-week period.

The images were compared with those of the nonsmokers (n = 28), whose criteria included a lifetime cannabis exposure of 10 times or less.

The results showed that the cannabinoid CB1 receptors were decreased by approximately 20% in cannabis smokers at baseline, compared with healthy controls, in cortical but not subcortical regions of the brain.

However, after 4 weeks of monitored abstinence, the PET scans of the 14 cannabis smokers showed some recovery in the areas that had shown a downregulation at baseline.

Although the results suggest no correlation with measures of craving or withdrawal, there was a negative correlation with years of abuse, according to Jussi Hirvonen, MD, PhD, lead author of the study.

"People who had abused cannabis for longer periods of time had smaller CB1 receptor distribution volume than people who had smoked for shorter periods of time," he explained.

"This could have been confounded by the subjects' age, because older subjects had more time to smoke cannabis than younger subjects. There was no correlation between distribution volume and age among healthy subjects."

The study is the first to demonstrate CB1 receptor downregulation in human chronic cannabis users, Dr. Hirvonen said.

"We have an imaging biomarker that is directly relevant to the effects of cannabis. We can use this biomarker to study the pathophysiology of various brain disorders known to be associated with cannabinoids."

Satoshi Minoshima, MD, PhD, who moderated the session, agreed that the identification of a this biomarker offers the promise of a better understanding of the effects of cannabis abuse on the brain.

"Cannabinoid receptor PET imaging is a relatively new field," said Dr. Minoshima, professor and vice chair of research in the Department of Radiology and Bioengineering and director of the Neuroimaging and Biotechnology Laboratory at the University of Washington in Seattle.

"This study is done well and provides neurochemical insights into cannabis dependency in human subjects. This is an initial study demonstrating downregulation, but I hope the authors will continue this research and correlate such neurochemical changes to clinical symptoms and addiction traits."

The research was supported by the Intramural Program of National Institute of Mental Health (project No. Z01-MH-002852-04). Dr. Hirvonen and Dr. Minoshima have disclosed no relevant financial relationships.

Society for Nuclear Medicine (SNM) 2011 Annual Meeting: Abstract 10. Presented June 5, 2011.

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