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substrates for SERT proteins. Stimulants that are not associated with IPAH, such as amphetamine and phentermine,5 are weak substrates for SERT.6 Chin et al1 correctly pointed out that our in vitro findings showed that d-amphetamine and METH are much more potent dopamine and norepinephrine transporter substrates when compared to their activities as SERTs. For example, the concentrations of d-amphetamine and METH as dopamine transporters having 50% of the effect compared to the control are approximately 25 nmol/L, whereas their corresponding values as SERTs are 1,765 and 736 nmol/L, respectively. Such data predict that pharmacologic doses of these drugs should not release 5-hydoxytryptamine (HT) in vivo. Consistent with this prediction, doses of d-amphetamine that elevate extracellular dopamine levels in the rat brain do not elevate extracellular 5-HT levels in nervous system tissue7 and do not increase 5-HT levels in plasma.8 In marked contrast, METH administration produces similar elevations in extracellular dopamine and 5-HT levels in the rat brain, and also increases plasma 5-HT levels.7,8 Our data indicate that, in the case of METH, the profile of transporter activity determined in vitro does not predict the profile of activity in vivo. It should be noted that the stimulant medications currently being prescribed for the treatment of attention deficit disorder (eg, amphetamine, d-amphetamine, and methylphenidate) and appetite control (eg, phentermine, diethylpropion, and phendimetrazine) have minimal activity at SERT9 and are taken at low oral doses, substantially reducing the possibility they will interact with SERT sites in human patients. Illicit METH, on the other hand, is often self-administered by smoked or IV routes where very high levels of drug would be expected to interact with SERTs in the brain and periphery. These considerations explain in part why METH, but not currently prescribed stimulants, might increase the risk of IPAH. In summary, our data indicate that METH is a SERT substrate in vivo. In conjunction with the data reported by Chin et al,1 the evidence provides further support for the hypothesis that SERT substrate activity is an important factor contributing to an increased risk of IPAH.4 In light of these findings, it will be essential to determine whether the recreational use of other illicit SERT substrates like 3,4-methylenedioxymethamphetamine (ecstasy) increases the risk of IPAH.10