Methamphetamine pharmacokinetics in human brain: Comparison with cocaine

Abstract

148

Objectives: Methamphetamine (METH) is one of the most addictive drugs of abuse. It produces larger and longer-lasting increases in brain dopamine (DA) than cocaine (COC) and is neurotoxic to DA cells. Here we measured the distribution and pharmacokinetics (PK) of METH in the human brain at tracer doses, comparing it with those of COC, and assessing the relationship between the PK of METH and the time course of METH’s reinforcing effects.

Methods: PET and [11C]d-methamphetamine and [11C]cocaine were used to measure brain METH and COC PK in 18 healthy men over 90 and 60 min periods, respectively. METH PK in striatum was compared to the time course of the ‘high’ from a pharmacological dose of METH and to dopamine transporter (DAT) availability (measured with [11C]cocaine).

Results: METH distributed throughout the brain whereas COC concentrated in striatum. Peak striatal uptake was higher for COC than for METH (0.0083±0.0012 vs 0.0065±0.0009 % dose/cc) and also occurred earlier (4.5±1.1 vs 9.4±1.5 min). Clearance was slower for METH than for COC (64 vs 25% of peak C-11 remained at 90 and at 60 min respectively). METH PK in striatum paralleled the time course of the self-reported ‘high’ after pharmacological doses of METH (Newton et al., 2006). Subjects with the highest striatal METH uptake also had the highest COC uptake (R=0.72, p=0.0005) and DAT availability correlated with METH uptake (R=0.6; p=0.007).

Conclusions: Widespread and long-lasting distribution of METH in the human brain may account for both its toxicity and the longer lasting behavioral effects relative to COC. Correlations between striatal METH and COC uptake suggest that a common variable governs the brain uptake to these two drugs.

Research Support: DOE-OBER; NIH/NIDA; NIH/NIAAA; NIH/GCRC.