Human pharmacology of the methamphetamine stereoisomers.
OBJECTIVE
To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers.


METHODS
In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for "intoxication," "good drug effect," and "drug liking") were obtained.


RESULTS
Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3-15.0 hours) than for d-methamphetamine (10.2-10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 +/- 23.4 beats/min, 13.5 +/- 18.5 beats/min, and 10.7 +/- 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 +/- 17.8 beats/min and 34.5 +/- 18.9 beats/min, respectively, versus 19.5 +/- 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 +/- 35.3 versus 30.3 +/- 24.9) and drug liking (47.7 +/- 35.1 versus 28.6 +/- 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures.


CONCLUSIONS
The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities.
Mendelson
John
J
Addiction Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St Luke's Hospital, San Francisco, CA 94110, USA. john.mendelson@cpmcri.org
Uemura
Naoto
N
Harris
Debra
D
Nath
Rajneesh P
RP
Fernandez
Emilio
E
Jacob
Peyton
P
Everhart
E Thomas
ET
Jones
Reese T
RT
D000328:Adult; D019969:Amphetamine-Related Disorders / Q000378:metabolism*; D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012107:Research Design; D012119:Respiration / Q000187:drug effects; D013237:Stereoisomerism
D000697:Central Nervous System Stimulants; D008694:Methamphetamine