Here we show that [11
C]d-methamphetamine is widely distributed in the human body and higher for some organs than for brain (per/cc tissue). The widespread distribution of methamphetamine in the various organs of the body is consistent with our prior findings in non human primates and rats in whom we showed a similar organ distribution of [11
and with immunocytochemistry studies in mice 
. In humans we show that the uptake of [11
C]d-methamphetamine was highest (per/cc tissue) in kidneys and lungs, intermediate in stomach, pancreas, liver, spleen and lower in brain and heart (). This distribution differs markedly from that of cocaine for which we showed that the highest uptake occurred in brain and the lowest in lungs 
The lung, along with the kidneys, had the highest [11
C]d-methamphetamine uptake and at peak approximately 24–31% of the injected dose was in the lung (assuming a weight of 1246 grams). The uptake of [11
C]d-methamphetamine in lung was very fast (peak 55 seconds) and is unlikely to just reflect its vascular perfusion since the peak concentration in lung was much higher than in arterial plasma and its clearance much slower (7 minutes vs 1.5 minutes). Lung accumulation could reflect uptake by monoamine transporters since [11
C]d-methamphetamine is a substrate for the dopamine, serotonin and norepinephrine transporters 
and/or non-specific binding. Of particular clinical relevance would be its uptake by the serotonin transporter since it is the one implicated in the higher risk for pulmonary hypertension seen in methamphetamine abusers 
. However, to our knowledge there is currently no data showing that the serotonin transporter is responsible for the uptake of methamphetamine in lungs.
A recent report revealed a greater risk of tuberculosis (TB) infection among methamphetamine users than non-users 
. Similarly a study of HIV-infected patients in Thailand reported that 40% of those also infected with TB had a history of methamphetamine use 
. Though this probably reflects improper nutrition and/or compromised immune function in methamphetamine abusers, we speculate that the high accumulation of methamphetamine in the lungs may also contribute by rendering pulmonary tissue more vulnerable to infections (or other insults). Studies to evaluate the association between methamphetamine abuse and TB merit more careful evaluation.
The high accumulation of methamphetamine in kidneys (at peak 7% of the injected dose was in the kidneys, assuming 305 grams for both kidneys) could reflect its high urine excretion, which is likely to reflect both its active secretion by renal tubule cells as well as its partition into an acidic urine (methamphetamine is a weak base) 
. It is estimated that 37–45% of an intravenous or smoked dose of methamphetamine is excreted in the urine as the parent drug and 6–7% as amphetamine within 72 hours of dosing (most of the excretion occurring within the first 20 hours) 
. This is consistent with our urine measurements which showed 10% of the injected dose was present in urine 90 minutes after injection of [11
In the pancreas (tail) the high uptake (per/cc tissue) of methamphetamine could reflect uptake by dopamine transporters and vesicular monoamine transporters, which are targets of methamphetamine and are highly expressed in pancreatic tissue 
and may mediate the rapid increases in insulin that follow acute methamphetamine administration 
. Though to our knowledge there are no published studies of methamphetamine abuse and diabetes, a preliminary report of abnormal glucose tolerance tests and aberrant insulin values in methamphetamine abusers supports this possibility 
Methamphetamine's accumulation in spleen was consistent with similar findings in rats and in non-human primates 
. In rodents methamphetamine impairs splenic lymphocyte function and produces immunosuppression 
, which could contribute to the higher rate of infections in methamphetamine abusers (i.e., TB, HIV). However, this interpretation requires demonstration of a causal relationship between local concentrations of methamphetamine and immunosuppression, which to our knowledge is currently not available.
The heart had lower methamphetamine uptake than other organs (2.6% injected dose at one min after injection) and its retention in heart was very short lasting. This was unexpected since cardiovascular events are among the most frequent medical complications reported in methamphetamine abusers (review 
). Thus our findings are consistent with the belief that methamphetamine's central and peripheral sympathomimetic effects rather than direct effects to myocytes, are responsible for its cardiotoxic effects (review 
). Nonetheless, the good temporal correspondence between methamphetamine's fast accumulation in heart (peaks 60 seconds) and the fast increases in blood pressure induced by this drug (peaks at 60 seconds after iv administration), 
suggests that methamphetamine may also directly affect cardiac tissue.
Brain uptake of methamphetamine was lower than in many of the organs (per cc of tissue), which could contribute to its clinical toxicity since significant organ accumulation will occur when the drug is used for recreational purposes. This is distinct from cocaine for which the brain uptake is higher than that observed in other organs 
. On the other hand methamphetamine's clearance from brain was very slow, which is likely to result in long lasting exposure of the brain to the sympathomimetic effects of this drug and contribute to its neurotoxicity. The neurotoxic effects of methamphetamine have been extensively documented and are believed to reflect both its vasoactive effects, which can result in ischemia and necrosis as well as its cathecholaminergic effects, which can result in damage to dopamine neurons, psychosis and seizures 
The pharmacokinetics of [11
C]d-methamphetamine in the stomach and liver were similar and were the slowest from all the organs. The hepatic accumulation of [11
C]d-methamphetamine was very high (22–24% injected dose; weight 1677 grams) and presumably represents methamphetamine and its metabolites. Some of the liver accumulation could reflect its uptake and excretion through the gallbladder 
. The unexpected high accumulation in stomach is likely to reflect the acid environment that favors the uptake of a basic drug such as methamphetamine. We note that the accumulation in stomach was quite variable among subjects, which could reflect in part differences in stomach acidification 
C]d-Methamphetamine's uptake and accumulation in lung was higher in AA than C. This is noteworthy since the prevalence rates of methamphetamine use in AA are much lower than in C 
. Cultural factors as well as market factors in drug access are likely to contribute to these differences. However, differences could also reflect genetic factors that make AA more vulnerable to the adverse effects of methamphetamine. Indeed the most consistent and robust findings in the genetics of drug abuse are that of “protective” genes that confer an enhanced sensitivity to the untoward effects of the drug (i.e., ALDH gene that leads to impaired metabolism of alcohol and protection against alcoholism) 
. Similarly in rats an enhanced sensitivity to the aversive effects of methamphetamine was associated with lower rates of drug self-administration. Interestingly, the serotonin transporter gene was implicated in this association 
The following are study limitations. First, PET measures the concentration of carbon-11 and cannot ascertain if the measures correspond to the drug or labeled metabolites. However, analysis of the plasma revealed that 70–72% of the parent compound remained at 60 minutes after injection indicating that the bulk of carbon-11 in most organs corresponded to the parent compound. Second, these studies were done at tracer doses of [11
C]d-methamphetamine, which raises the question of whether the pharmacokinetics of a tracer dose reflects that of a pharmacologically active dose (i.e., 0.5 mg/kg). However, the fact that the pharmacokinetics of d-methamphetamine in the baboon brain were not altered at behaviorally active doses 
suggests that tracer doses reflect those of pharmacological doses. Third, from these studies we cannot determine whether methamphetamine's uptake (methamphetamine is a substrate for monoamine transporters) is by specific reuptake sites or non-specific accumulation. Fourth, methamphetamine is a mixture of levorotatory and dextrorotatory isomers and here we report only on d-methamphetamine. Though this is the predominant form of methamphetamine sold in the streets some forms contain l-methamphetamine and thus one could question whether this could result in a different organ distribution from that of d-methamphetamine. This is unlikely since we had previously shown no differences in the uptake and distribution of carbon-11 labeled l- methamphetamine and d- methamphetamine in non-human primates 
. Finally, the sample size was small and thus we are treating the differences in pulmonary accumulation of [11
C]d-methamphetamine between AA and C as preliminary and in need of replication.
In summary this study reports widespread distribution of methamphetamine throughout most body organs, which is likely to contribute to the serious medical conditions that affect methamphetamine users. It also identifies differences in pulmonary uptake of methamphetamine between AA and C that merits further investigation.