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Methamphetamine and Idiopathic Pulmonary Arterial Hypertension : Role of the Serotonin Transporter FREE TO VIEW

Richard B. Rothman, MD, PhD; Michael H. Baumann, PhD, FCCP
Author and Funding Information

National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD

Correspondence to: Richard B. Rothman, MD, PhD, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Clinical Psychopharmacology Section, 5500 Nathan Shock Dr, Baltimore, MD 21224; e-mail: rrothman@mail.nih.gov



Chest. 2007;132(4):1412-1413. doi:10.1378/chest.07-0235
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To the Editor:

In a recent article in CHEST (December 2006),1Chin et al reported that methamphetamine (METH) abuse significantly increases the risk of developing idiopathic pulmonary arterial hypertension (IPAH) [odds ratio, 11.6]. Their findings add IPAH to the list of serious medical complications associated with METH abuse.2The data, while requiring confirmation by a larger epidemiologic investigation,3 raise interesting questions as to what pharmacologic mechanism might underlie the link between METH and IPAH. We suspect at least two critical factors contribute to such a mechanism: (1) the preferential interaction of METH with serotonin transporters (SERTs) in vivo; and (2) the high doses of illicit METH that are typically self-administered.

Our previous work4has demonstrated that medications known to increase the risk of IPAH (ie, fenfluramine, d-fenfluramine, and aminorex) share the common ability to serve as potent 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 tissue,7and 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.78 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

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Chin, KM, Channick, RN, Rubin, LJ (2006) Is methamphetamine use associated with idiopathic pulmonary arterial hypertension?Chest130,1657-1663. [PubMed] [CrossRef]
 
Romanelli, F, Smith, KM Clinical effects and management of methamphetamine abuse.Pharmacotherapy2006;26,1148-1156. [PubMed]
 
Willers, ED, Newman, JH New risks for pulmonary hypertension: need for a large epidemiologic study.Chest2006;130,1633-1635. [PubMed]
 
Rothman, RB, Ayestas, MA, Dersch, CM, et al Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates: implications for primary pulmonary hypertension.Circulation1999;100,869-875. [PubMed]
 
Rich, S, Rubin, L, Walker, AM, et al Anorexigens and pulmonary hypertension in the United States: results from the Surveillance of North American Pulmonary Hypertension.Chest2000;117,870-874. [PubMed]
 
Rothman, RB, Baumann, MH Monoamine transporters and psychostimulant drugs.Eur J Pharmacol2003;479,23-40. [PubMed]
 
Baumann, MH, Ayestas, MA, Dersch, CM, et al Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.Synapse2000;36,102-113. [PubMed]
 
Zolkowska, D, Rothman, RB, Baumann, MH Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease.J Pharmacol Exp Ther2006;318,604-610. [PubMed]
 
Rothman, RB, Baumann, MH Therapeutic potential of monoamine transporter substrates.Curr Top Med Chem2006;6,1845-1859. [PubMed]
 
Setola, V, Hufeisen, SJ, Grande-Allen, KJ, et al 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cellsin vitro.Mol Pharmacol2003;63,1223-1229. [PubMed]
 

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References

Chin, KM, Channick, RN, Rubin, LJ (2006) Is methamphetamine use associated with idiopathic pulmonary arterial hypertension?Chest130,1657-1663. [PubMed] [CrossRef]
 
Romanelli, F, Smith, KM Clinical effects and management of methamphetamine abuse.Pharmacotherapy2006;26,1148-1156. [PubMed]
 
Willers, ED, Newman, JH New risks for pulmonary hypertension: need for a large epidemiologic study.Chest2006;130,1633-1635. [PubMed]
 
Rothman, RB, Ayestas, MA, Dersch, CM, et al Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates: implications for primary pulmonary hypertension.Circulation1999;100,869-875. [PubMed]
 
Rich, S, Rubin, L, Walker, AM, et al Anorexigens and pulmonary hypertension in the United States: results from the Surveillance of North American Pulmonary Hypertension.Chest2000;117,870-874. [PubMed]
 
Rothman, RB, Baumann, MH Monoamine transporters and psychostimulant drugs.Eur J Pharmacol2003;479,23-40. [PubMed]
 
Baumann, MH, Ayestas, MA, Dersch, CM, et al Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.Synapse2000;36,102-113. [PubMed]
 
Zolkowska, D, Rothman, RB, Baumann, MH Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease.J Pharmacol Exp Ther2006;318,604-610. [PubMed]
 
Rothman, RB, Baumann, MH Therapeutic potential of monoamine transporter substrates.Curr Top Med Chem2006;6,1845-1859. [PubMed]
 
Setola, V, Hufeisen, SJ, Grande-Allen, KJ, et al 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cellsin vitro.Mol Pharmacol2003;63,1223-1229. [PubMed]
 
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