Methamphetamine’s powerful addictive properties, its toxicity and its ready availability combine to create a sense of urgency to understand its behavioral and toxic effects. At the same time, reports that the rate of METH abuse among African Americans is lower than that for Caucasians has led us to question whether there are differences in bioavailability or PK that mediate this effect. The major findings from this study are that (1) d-methamphetamine has a relatively rapid and persistent distribution across brain regions with slow clearance from gray matter and no observable clearance from white matter regions which distinguish it from cocaine; (2) the kinetics in ventral striatum (where the nucleus accumbens is located) follow a similar time course to the ‘high’ reported from a pharmacological dose of d-methamphetamine (data from Newton et al., 2006
); (3) Caucasians and African Americans do not differ in the PK or bioavailability of [11
C]d-methamphetamine in brain though the two groups differ in [11
C]cocaine’s PK and bioavailability and; (4) METH uptake in striatum but not the cerebellum over the time course of the study correlated with DAT availability. This suggests that differences in DAT availability between subjects may account for some of the inter-subject variability in METH exposure in striatum, which is the main target for METH dopaminergic effects. Since METH’s dopaminergic effects are implicated in its reinforcing properties, the differences in DAT availability is likely to contribute to variability in METH’s reinforcing effects.
C]d-Methamphetamine distributed widely in the human brain with high and persistent uptake in both subcortical and cortical areas (). This is similar to our recent findings in the non-human primate brain (Fowler et al., 2007
) and to earlier studies in rat brain (O’Neil et al., 2006
; Segal et al., 2005
) after intravenous MET administration and to human autopsy samples from methamphetamine abusers (Kalasinksy et al., 2001
) but different from [11
C]cocaine (). The highest peak uptake of METH was in the putamen (average peak uptake ~ 0.0065%/cc) whereas the lowest peak uptake occurred in the white matter (~ 0.003%/cc). After iv administration, 7-8% of the injected dose accumulated in the brain within 10 minutes. Though the present studies were done at tracer doses, we can use this information to estimate that a typical abused dose of 30 mg of METH would result in a brain accumulation of ~ 2.5 mg of METH (~14 microM). Methamphetamine’s high concentration and persistence in brain and its ability to stimulate release and inhibit reuptake of DA (Rothman et al., 2001
) would be predicted to lead to an elevation of DA (and other neurotransmitters) potentially leading to its intense behavioral effects and producing oxidative stress and damage throughout the brain (Volz et al., 2007
Several studies have documented neurochemical, metabolic and morphological abnormalities in methamphetamine abusers and in animals exposed to methamphetamine that are not limited to brain regions containing DA cells and their terminals, implicating non-DA mechanisms of METH toxicity (Ernst et al., 2000
; Volkow et al., 2001a
; Thompson t al., 2004
; Chung et al., 2007
; Kuczenski et al., 2007
). The present study which documents the METH distributes to many brain regions () as well as prior studies documenting the relatively even distribution of METH in autopsy samples from methamphetamine abusers (Kalisinsky et al, 2001
) adds to the increasing evidence that the pharmacological effects of METH are complex and involve different neurotransmitters and neuromodulators (Weinshenker et al., 2007
) and suggests an association with the widespread disposition of the drug. New evidence in postmortem brains of METH abusers shows the presence of the lipid peroxidation products, 4-hydroxynonenal and malondialdehyde that is most prominent in striatum (caudate), intermediate in frontal cortex and absent in cerebellum (Fitzmaurice et al., 2006
). We note that the distribution of METH differs from that of cocaine, which concentrates mostly in striatum and, unlike METH, clears rapidly () (Fowler et al., 1989
). Thus the brain exposure and presumably the neurotoxicity of METH are expected to differ from those of cocaine.
In this study we documented peak concentration of METH in putamen at ~ 9 minutes after its intravenous administration (Figures and ). This tracks the onset of peak behavioral effects produced by smoked, and intravenous METH, which occur within 9-18 min of its administration (Newton et al., 2006
; Cook et al., 1993
). The rapid rate of entry into the brain is likely to contribute to the powerful reinforcing effects of METH since the rate at which drugs of abuse get into the brain plays a key role in reinforcement; the faster the uptake the stronger its reinforcing effects (Balster and Schuster, 1973
). This, in turn, explains why smoking and intravenous injection are the routes of administration that produce the most pleasurable responses to drugs of abuse (Volkow et al., 2000
). Moreover the correspondence between the fast uptake of METH in the ventral striatum and the time course for the self-reports of ‘high’ after intravenous METH (Newton et al., 2006
) suggests a relationship between METH’s pharmacokinetics and its pharmacodynamic effects including the time course of its reinforcing effects in humans. The faster rate of uptake of cocaine vs METH in brain corresponds well with the fact that the self-reported ‘high’ occurs faster after intravenous cocaine (4-6 minutes (Volkow et al., 1997
) than after intravenous METH (approximately 9 min (Figures and )).
We found that the clearance of METH also roughly corresponded with the temporal course of the decline in the experience of the ‘high’. This indicates that it is the PK of the drug in the brain, which is the important variable in determining the duration of its behavioral effects when administered at a pharmacologically active dose. The longer duration of the METH in the brain is associated with the long lasting ‘high’ reported previously (Newton et al., 2006
). The temporal relationship between the time courses of the uptake and clearance of [11
C]dmethamphetamine in the brain and the time course of the intensity of the ‘high’ is similar to the relationship between these two variables for cocaine (Volkow et al., 1997
). The much slower brain clearance of METH relative to cocaine is likely to reflect differences in bioavailability and non-specific effects (Fowler et al., 2007
). The longer duration of action along with its potent effects in raising DA are likely to contribute to the greater neurotoxicity to DA cells reported for METH than for cocaine. Indeed imaging studies have shown decrements in DAT in METH but not in cocaine abusers (Volkow et al., 2001b
; Volkow et al., 1996
). We note the terminal half life of d-methamphetamine in human plasma after iv was reported to be 13.1 hr (Cook et al., 1993
) which is far longer than the brain clearance rate or the arterial clearance, which we report here. However, the PET study covered the early part of the time curve from a few seconds to 90 minutes whereas the plasma half life reported in the previous study (Cook et al, 1993
) was measured during a 2 minute to 48 hour period capturing the terminal clearance phase. Interestingly, the putamen to plasma ratio in the human peaked 16:1 at 20 minutes post injection and plateaued thereafter (data not shown) which is comparable to the published rat PK for d-METH which also peaked at 20 minutes reaching a similar value of 13:1 (Riviere et al, 2000
An important but not well understood aspect in the epidemiology of METH abuse is the low prevalence rates in African Americans relative to Caucasians (Sexton et al., 2005
; Iritani et al., 2007
). Several explanations have been proposed including a higher preference and accessibility to cocaine in African Americans, dislike for METH’s long-lasting stimulant effects and limited access to METH (Sexton et al., 2005
). However, we questioned the possibility that biological factors affecting METH bioavailability and PK (i.e metabolism, excretion) could contribute to these differences. The similarities in the regional distribution and PK of METH in brain between African Americans and Caucasians (; ) indicates that factors other than differences in bioavailability underlie the lower use of METH among African Americans. In contrast, there were significant differences between the ethnic groups for cocaine; cocaine peaked later and cleared more slowly in African Americans than in Caucasians and brain distribution volumes (all regions) for cocaine were also higher for African Americans ( and ). Although we do not know whether there is any clinical significance due to these differences, this surprising observation raises the question of whether differences in bioavailability between Caucasians and African Americans have any epidemiological or clinical manifestation. It also merits further investigation in a larger group of subjects and highlights the importance of considering and reporting ethnicity as a variable in clinical research studies and in matching ethnicity between control and experimental subjects.
The heterozygous deletion of DAT attenuates the behavioral effects of METH (Fukushima et al., 2007
) suggesting that DAT (as well as VMAT2) play a role in its neurotoxicity (Fumagalli et al., 1998
; Fumagalli et al., 1999
). Given the role of the DAT in the behavioral effects of METH and assuming that higher METH exposure is an important variable in the behavioral effects of the drug, we examined whether there would be an association between DAT availability (as measured using the DVR-1 with [11
C]cocaine) and METH exposure using the area under the time-activity curve (AUC) for the putamen as the measure of METH exposure. Interestingly, the AUC varied by almost 2-fold for all individuals. Subjects with the highest AUC for METH in the putamen also had the highest DAT availability (). We note that the AUC for the cerebellum for METH does not correlate with DAT availability suggesting a specific association with striatum and not a global effect. These data suggest that individual DAT availability in striatum may play a role in the variability in individual’s METH exposure.
There are potential study limitations that need to be addressed. For example, we measured METH PK at tracer doses whereas METH abusers use the drug at a typical dose of 0.5 mg/kg. This raises a question as to whether the PK of METH measured with a tracer dose of [11
C]d-methamphetamine mimics the PK of a pharmacological dose that has behavioral effects. However, there is evidence that this is a valid assumption based on the fact the PK of [11
C]dmethamphetamine in the baboon at tracer and at pharmacological doses did not differ (Fowler et al., 2007
). For this study we also studied healthy, non-abusing controls rather than METH abusers. We felt that it was important to investigate these relationships in a control, non-abusing population to avoid introducing other variables such as the structural and neurochemical abnormalities (including long lasting decreases in DAT), which are known to occur in the METH abuser (Volkow et al., 2001b
). We note that this study methodology could be adapted to the METH abuser after an adequate washout period to assure that the DAT availability measurement would not be influenced by METH occupancy of the DAT.
Another issue that needs to be addressed is the extent to which the C-11 in the brain reflects METH and not labeled metabolites or a combination of [11
C]d-methamphetamine and its labeled metabolites. We analyzed the arterial plasma of each subject for the percent of the total C-11 that was in the form of the parent compound. We note that the appearance of labeled metabolites in plasma is slow so that input to the brain is mostly [11
C]d-methamphetamine (). In addition, a major metabolite of METH is amphetamine, which arises from N-demethylation. Since [11
C]d-methamphetamine is labeled in the N-methyl group, amphetamine would not be detected. Similarly, for [N-11
C-methyl]cocaine, the only labeled molecule that can penetrate the brain is [11
C]cocaine (Fowler et al., 1989
In summary, in the first study of METH PK in the normal human brain, we found widespread and long-lasting distribution of METH, which parallels its long lasting behavioral effects. Widespread distribution of METH in brain is also consistent with reports that METH’s effects on brain chemistry and structure go beyond brain regions highly innervated with DA (i.e parietal cortex, white matter). Contrary to our original hypothesis, we found no difference in METH PK and bioavailability between Caucasians and African Americans suggesting that other variables need to be considered in accounting for the lower rate of METH abuse in African Americans. However, these comparative studies also revealed significant differences between Caucasians and African Americans in [11C]cocaine PK and bioavailability in brain which merit further investigation. Our finding that individuals with the highest striatal METH exposure also had the highest DAT availability suggests that DAT levels regulate the brain uptake of METH.