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Yoshimoto Sekine, MD, PhD; Yasuomi Ouchi, MD, PhD; Nori Takei, MD, PhD, MSc; Etsuji Yoshikawa, BA; Kazuhiko Nakamura, MD, PhD; Masami Futatsubashi, BA; Hiroyuki Okada, BA; Yoshio Minabe, MD, PhD; Katsuaki Suzuki, MD, PhD; Yasuhide Iwata, MD, PhD; Kenji J. Tsuchiya, MD; Hideo Tsukada, PhD; Masaomi Iyo, MD, PhD; Norio Mori, MD, PhD

Arch Gen Psychiatry. 2006;63:90-100.

Context  In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans.

Objective  To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers.

Design  Case-control analysis.

Setting  A hospital research center.

Participants  Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community.

Interventions  The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([¹¹C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables.

Main Outcome Measures  The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [¹¹C](+)McN-5652 distribution volume.

Results  Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers.

Conclusions  Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

Author Affiliations: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan (Drs Sekine, Takei, Nakamura, Minabe, Suzuki, Iwata, Tsuchiya, and Mori); Positron Medical Center, Hamamatsu Medical Center, Hamakita, Japan (Dr Ouchi); Division of Psychological Medicine, Institute of Psychiatry, London, England (Dr Takei); Central Research Laboratory, Hamamatsu Photonics KK, Hamakita (Dr Tsukada and Messrs Yoshikawa, Futatsubashi, and Okada); and Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan (Dr Iyo).

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