International - Brain Regions Shrink in Heavy Pot Users

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Brain Regions Shrink in Heavy Pot Users


MELBOURNE, June 2 -- The brain on drugs -- specifically marijuana -- may be significantly smaller in some areas, researchers here said. Action Points

• Explain to interested patients that possible long-term toxic effects of marijuana on the brain have been a subject of controversy.
• Note that this study shows significant changes in the volume of two regions of the brain among long-term heavy users of the drug.
• Point put that this study cannot determine causality.

In a small cross-sectional study using magnetic resonance imaging, the hippocampus and amygdala in men who were heavy long-term users of the drug were significantly smaller than those in control volunteers, according to Murat Yücel, Ph.D., of the University of Melbourne, and colleagues.

Both regions are rich in cannabinoid receptors and might be expected to be affected if heavy long-term use of marijuana were toxic, Dr. Yücel and colleagues said in the June issue of Archives of General Psychiatry.

The results "suggest that heavy daily use might indeed be toxic to human brain tissue," they concluded.

While other studies have looked at changes in the brain associated with use of marijuana, they have not been found before, perhaps because instruments were not sensitive enough or the use of marijuana wasn't heavy enough, the researchers said.

For this study, the researchers enrolled 15 men who had smoked more than five joints a day for more than 10 years, but who did not have other co-morbid drug use or neurological or psychiatric illness.

On average, the men had used marijuana for nearly 20 years.

They were contrasted with 16 matched controls who did not use the drug.

The volunteers took tests for subthreshold psychiatric symptoms and verbal learning ability, as well as being scanned in a high-resolution, three-Tesla MRI machine.

Analysis of the MRI scans showed:

• Marijuana users had a reduction in the volume of the hippocampus of 12.1% in the left and 11.9% in the right, compared with controls. The difference was statistically significant at P=0.001.
• They also had a reduction of 6% in the left amygdala and 8.2% in the right amygdala, compared with controls. Again the differences were significant at P=0.001.
• Within the marijuana-using group, the magnitude of the hippocampal reduction was significantly greater (P=0.02) than the reduction in the amygdala.
• Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous decade, and the association was significant at P=0.01.

The marijuana users did not suffer any mental illness at the time of testing. Nevertheless, they reported significantly higher (P=0.001) positive symptoms on the Scale for the Assessment of Positive Symptoms and negative symptoms (on the corresponding scale) than did controls.

The volume of the left hippocampus and cumulative exposure to marijuana were significantly associated with positive symptom scores, at P<0.001 and P=0.048, respectively, the researchers found.

On the Rey Auditory Verbal Learning Test, the marijuana users did significantly worse than controls, both on the sum of words learned over five trials and one free recall after 20 minutes. The differences were significant at P<0.001 and P=0.009, respectively.

On the other hand, those deficiencies were not correlated with any of the volume changes, Dr. Yücel and colleagues said.

The researchers said the effect size of the volume reductions was large, but it's still not clear whether the changes reflect neuronal or glial loss, a change in cell size, or a reduction in synaptic density.

The marijuana users were required to refrain from smoking the drug for only 12 to 24 hours before the MRI test, making it unlikely that the observed changes reflect recent use, the researchers said.

"We are unaware of any evidence that suggests that the hippocampus and amygdala can change in volume by 6% to 12% in short periods," they said.

The study is limited by the small sample size, they said, although it was unique in the heavy long-term use of the drug by participants who did not abuse other drugs nor have mental or neurologic disorders.

They also acknowledged that the careful screening for current and past history of mental disorders may have selected out an unusual subset. "One speculation is that the present participants were less genetically vulnerable to developing a psychotic disorder subsequent to cannabis use, allowing them to smoke heavily for many years."

"As such, we conducted the first, to our knowledge, 'pure' examination of the effects of heavy and protracted exposure to cannabis in humans," Dr. Yücel and colleagues said.

The study was supported by the Clive and Vera Ramaciotti Foundation, the
Schizophrenia Research Institute, the National Health and Medical Research Council, the Colonial Foundation, a J.N. Peters Fellowship and National Health and Medical Research Council C.J. Martin Fellowship, and Neurosciences Victoria. The researchers said they had no conflicts.

By Michael Smith, North American Correspondent, MedPage Today
Published: June 02, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
http://www.medpagetoday.com/Psychiatry/Addictions/9679

Primary source: Archives of General Psychiatry
Source reference:
Yücel M, et al "Regional brain abnormalities associated with long-term heavy cannabis use" Arch Gen Psychiatry 2008; 65(6): 694-701.