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(Chest. 2006;130:1657-1663.)
© 2006 American College of Chest Physicians

Is Methamphetamine Use Associated With Idiopathic Pulmonary Arterial Hypertension?

Kelly M. Chin, MD; Richard N. Channick, MD, FCCP and Lewis J. Rubin, MD, FCCP

* From the Department of Internal Medicine (Dr. Chin), Division of Pulmonary and Critical Care Medicine, St. Paul University Hospital, Dallas, TX; and Department of Internal Medicine (Drs. Channick and Rubin), Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, CA.

Correspondence to: Richard Channick, MD, 9330 Campus Point Dr, MC 7381, La Jolla, CA 92037; e-mail: rchannick{at}ucsd.edu

Abstract

Background: Amphetamine, methamphetamine, and cocaine are suspected of being pulmonary hypertension risk factors based on a small number of case reports along with pharmacologic similarities to fenfluramine, a diet drug associated with pulmonary arterial hypertension (PAH). We sought to determine whether rates of stimulant use are increased in patients believed to have idiopathic PAH compared with patients with PAH and known risk factors and patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Methods: In this retrospective study, rates of stimulant use were determined for 340 patients with idiopathic PAH, PAH and known risk factors, or CTEPH seen between November 2002 and April 2004. "Stimulant" use was defined as any reported use of amphetamine, methamphetamine, or cocaine. Odds of stimulant use were calculated using a polychotomous logistic regression model.

Results: A history of stimulant use was found in 28.9% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor, and 4.3% of patients with CTEPH. After adjustment for differences in age, patients with idiopathic PAH were 10.14 times (95% confidence interval, 3.39 to 30.3; p < 0.0001) more likely to have used stimulants than patients with PAH and known risk factors, and 7.63 times (95% confidence interval, 2.99 to 19.5; p < 0.0001) more likely to have used stimulants than patients with CTEPH.

Conclusions: Patients with idiopathic PAH are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension.

Key Words: illicit drugs • methamphetamine • pulmonary hypertension • risk factors

Pulmonary arterial hypertension (PAH) is a life-threatening and potentially fatal disorder. While some risk factors for PAH have been identified, many cases remain idiopathic. Amphetamines, cocaine, and other stimulants have been considered "possible" or "very likely" risk factors,1 but evidence supporting this conclusion is limited. There are a small number of case reports implicating cocaine23 and methamphetamine4 in the development of pulmonary hypertension, but stimulant use as a PAH risk factor has not been investigated in detail.

Over the last decade, the use of stimulants for the treatment of attention deficit disorder has increased approximately threefold.5 Illicit stimulant use has increased as well, with an estimated 5.2% of the population reporting "ever" use of methamphetamine, and 0.6% reporting use in the last year.6 Frequency of methamphetamine and amphetamine use varies by geographic location. Among persons aged ≥ 12 years, rates of use in the last year in western states (including California) were highest, ranging from 0.98 to 2.21%, while rates in the northeast were lowest, with most states having rates of use from 0.04 to 0.32%.7

In order to determine whether rates of stimulant use were increased in idiopathic PAH compared with other forms of pulmonary hypertension, we performed a retrospective study evaluating amphetamine, methamphetamine, and cocaine use in patients with pulmonary hypertension seen at a large pulmonary hypertension referral center. A portion of these results were previously published in abstract form.8

Materials and Methods

This was a retrospective study conducted at the University of California at San Diego, Thornton Hospital, La Jolla, CA. The study included all patients > 18 years old with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) seen over an 18-month period (November 2002 to April 2004) in the pulmonary hypertension clinics. Information on demographics, hemodynamics, pulmonary hypertension etiology, race, and prior stimulant drug use was abstracted from medical records. Any use of amphetamine, methamphetamine, or cocaine was considered a positive history of "stimulant" use, as patients were routinely asked about the use of these drugs during the initial history and physical examination. Use of other amphetamine-like drugs was not included, as reliable information was not available for many patients.

Patients were categorized by their treating pulmonary hypertension specialist based on the 2003 revised clinical classification,1 and based on this diagnosis they were placed into one of three groups: idiopathic PAH, PAH with known risk factors, and CTEPH. Patients with other forms of pulmonary hypertension such as pulmonary hypertension related to lung disease or left-heart disease were excluded from the study (Table 1 ). All patients were required to have undergone cardiac catheterization for the initial diagnosis, except those with either a ventricular septal defect or patent ductus arteriosus. For these patients, echocardiographic evidence of the congenital heart abnormality plus pulmonary hypertension was accepted.


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  		Table 1.. Patients Excluded From Analysis

 
Patients with either familial PAH or PAH and one of the "associated" conditions listed in the 2003 revised clinical classification1 of pulmonary hypertension were considered to have PAH with known risk factors. This group included familial PAH, PAH associated with collagen vascular disease, PAH associated with congenital systemic-to-pulmonic shunts, and PAH associated with the use of fenfluramine or dexfenfluramine. HIV- and portal hypertension-associated PAH patients were excluded because illicit drug use is a risk factor for HIV and liver disease. Patients with PAH and none of the above risk factors were categorized as having idiopathic PAH. Finally, patients with angiographically proven thromboembolic disease were categorized as having CTEPH.

This study received approval by the University of California, San Diego Institutional Review Board, including approval for a waiver of informed consent. This waiver required that there be no disclosure of protected health information and that patient information be "de-identified" at the earliest possible date.

Statistical Analysis
Statistical analysis was performed using a logistic regression model that included all three groups (polychotomous logistic regression). Age, gender, and race were included in the model as potential confounders due to associations between these variables and type of pulmonary hypertension and the possibility that they may also be associated with stimulant drug use.6 Interaction between stimulant drug use and age, gender, and race was tested using the log likelihood method. After testing for interaction, these potential confounders were removed from the model through backward elimination if the association (odds ratio) between stimulant use and type of pulmonary hypertension changed by < 10%. Statistical software (NCSS 2004; NCSS; Kaysville, UT) was used for the analysis including tests for collinearity; p < 0.05 was considered significant.

Results

Six hundred fourteen patients with a diagnosis of possible or definite pulmonary hypertension were seen over an 18-month period. One hundred eighty-three patients were excluded from the analysis because inclusion criteria were not met, including 42 patients with left-heart disease, 42 patients with lung disease, 25 patients with other forms of pulmonary hypertension, 39 patients with normal hemodynamics at catheterization, and 35 patients excluded for other reasons; additional details are given in Table 1. Of the remaining 431 patients with PAH or CTEPH, 91 patients (21%) were excluded due to incomplete or missing stimulant use histories. Rates of complete stimulant use histories were significantly higher in the idiopathic PAH group (87%) than in the group with PAH and a known risk factors (79%), and in the CTEPH group (74%). The final sample of 340 patients included 97 patients with idiopathic PAH, 106 patients with PAH and known risk factors, and 137 patients with CTEPH.

More women than men were seen in all patient groups, with women making up 56.2% of the CTEPH group, 72.2% of the idiopathic PAH group, and 88.7% of the group with PAH and known risk factors (Table 2 ). Patients in the CTEPH group were oldest, with a mean age of 53.0 years, compared with 49.1 years for those with PAH and known risk factors, and 47.1 years for those with idiopathic PAH.


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  		Table 2.. Demographics by Diagnosis Group

 
Thirty-eight patients reported exposure to a stimulant-type drug, including 28 patients with a diagnosis of idiopathic PAH, 6 patients with CTEPH, and 4 patients with PAH and known risk factors (Table 3 ; Fig 1 ). Methamphetamine use was reported most frequently, with 23 patients reporting methamphetamine use alone and 8 patients reporting use of both methamphetamine and cocaine. Three patients had taken amphetamines illicitly, and two others reported amphetamine use as a diet pill (although one patient had also used cocaine). Cocaine use alone was uncommon, with only three patients describing cocaine use without methamphetamine or amphetamine use. Route of exposure was described for 11 patients, including 2 patients who had used stimulants IV, and 9 patients who had used stimulants through non-IV routes (inhaled, smoked, or oral).


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  		Table 3.. Specific Stimulants Taken by Pulmonary Hypertension Group*

 

Figure 1
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  		Figure 1.. As shown, 28.9% of patients with idiopathic PAH reported prior stimulant use, compared with 3.8% of patients with PAH associated with other risk factors, and 4.4% of patients with CTEPH (p < 0.0001 for comparison between idiopathic PAH and PAH with known risk factors, and between idiopathic PAH and CTEPH). Graph shows proportion and 95% confidence interval.

 
Patients with reported stimulant use were significantly younger than patients without reported use (mean age, 44.5 years vs 50.9 years; p = 0.006), but no significant differences in rates of use by race or gender were seen. Duration of use was not available in all cases and was reported only as "long term" or "frequent" in others, but 15 patients did report a general duration of use ranging from 6 months to 25 years; Tables 4, 5 provide additional details. Two patients had positive toxicology screen results at diagnosis, and two other patients required hospitalizations for PAH exacerbations after resuming drug use despite initial improvement with treatment.


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  		Table 4.. Idiopathic PAH: Drug Use Histories

 

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  		Table 5.. PAH With Risk Factors and CTEPH: Drug Use Histories

 
Prior to adjustment for potential confounders, patients with idiopathic PAH were significantly more likely to have a history of stimulant use than patients in either of the comparison groups, with an odds ratio of 10.35 (95% confidence interval, 3.47 to 30.8; p < 0.0001) for idiopathic PAH compared with PAH and known risk factors, and 8.86 (95% confidence interval, 3.5 to 22.4; p < 0.0001) for idiopathic PAH compared with CTEPH (Table 6 ). The odds ratios changed only modestly with the addition of age, gender, and race into the model, and no significant interaction between these possible confounders and stimulant drug use was seen. After backwards elimination using the prespecified criteria, gender and race were removed from the model, and age was retained due to a modest decrease in the odds ratio for CTEPH compared with idiopathic PAH patients. The final age-adjusted odds ratios for a prior stimulant history were 10.14 (95% confidence interval, 3.39 to 30.3; p < 0.0001) for idiopathic PAH compared with AH with known risk factors, and 7.63 (95% confidence interval, 2.99 to 19.5; p < 0.0001) for idiopathic PAH compared with CTEPH. Odds ratios for methamphetamine use were also significant. Amphetamine use and cocaine use alone were too infrequent to evaluate separately.


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  		Table 6.. Odds of Stimulant Use in Idiopathic PAH, PAH With Known Risk Factors, and CTEPH*

 
Although HIV and portal hypertension patients were excluded from the study, data on rates of stimulant use were recorded for these groups. Eighty-nine percent (eight of nine patients) with HIV and PAH reported prior stimulant use, and 20% (one of five patients) with portal hypertension had taken stimulants. Due to small numbers as well as the lack of an appropriate control group, formal statistical analysis was not performed.

Discussion

The central finding of this study was that methamphetamine exposure appears to be strongly associated with idiopathic PAH. Patients with idiopathic PAH were approximately 10 times more likely to have a history of stimulant use than patients with PAH and known risk factors, and almost 8 times more likely to have a history of stimulant use than patients with CTEPH, after adjustment for age. These ratios are similar to those found in studies of fenfluramine use. For example, the Surveillance of North American Pulmonary Hypertension study9 found an odds ratio of 7.5 for > 6 months of fenfluramine use comparing primary pulmonary hypertension patients to those with secondary pulmonary hypertension, and the International Primary Pulmonary Hypertension study10 found an odds ratio of 6.3 for "any anorexigen use" in primary pulmonary hypertension patients compared with control subjects. Rates of cocaine use alone were too infrequent to make meaningful conclusions but were included in the primary analysis, as stimulant use was defined prior to data collection.

Because of methodologic limitations inherent in a retrospective chart review study, these results must be considered preliminary. Potential limitations include missing data and questions about the acceptability of the control groups. Pulmonary hypertension subtype is generally not known definitively at the time of initial consultation, and we thus expected to find similar rates of missing data. However, 21% of patients with PAH and risk factors and 26% of patients with CTEPH had missing or incomplete stimulant use histories, compared with only 13% of patients believed to have idiopathic PAH. Negative stimulant-use histories may have been more likely to be recorded as "noncontributory" or "unremarkable" (considered incomplete), but this does not completely explain the different rates of missing data.

Another concern is that patients with CTEPH may be referred from a wider geographic region, potentially affecting rates of stimulant use. The use of a second control group made up of patients with PAH associated with other risk factors should be reassuring, as the referral pattern in these patients is generally similar to that of patients with idiopathic PAH. Exclusion of individual subgroups within the PAH with risk factors group (for example, excluding those with fenfluramine use) also did not appreciably change the calculated odds ratios.

A final concern is that other chronic illnesses in the two comparison groups might somehow decrease the rates of stimulant drug use below that of a normal population. This is a potential factor, though the rate of methamphetamine use in our two control populations was only slightly lower than nationally reported rates. Further, in most cases the symptoms and disability from pulmonary hypertension are more severe than the symptoms of any associated condition.

Despite these methodologic limitations, the finding that 28 of 97 patients with idiopathic PAH have a history of stimulant use is important and suggestive of an association. The far-lower rates of stimulant use found in the two comparison groups with pulmonary hypertension add strength to this observation and suggest that these findings are not just related to the geographic location or some other aspect of our patient population. While the results of retrospective studies may be considered preliminary and less robust than more formal case-control studies, they can provide some evidence of an association along with the rationale needed to conduct additional studies. For example, the observation by Brenot et al11 of frequent anorexigen use in a population with primary pulmonary hypertension coupled with increasing use of these medications led to the performance of the International Primary Pulmonary Hypertension study,10 definitively linking anorexigen use with the development of PAH.

The mechanisms through which methamphetamine use could lead to pulmonary hypertension are unknown, and in vivo studies evaluating the effects of stimulants on the pulmonary vasculature are limited. One small study12 showed increased pulmonary arterial pressures after methamphetamine administration in humans, while another study13 showed that cocaine administration failed to increase pulmonary arterial pressures.

Similarities in pharmacology between amphetamines and the diet drug fenfluramine, a known risk factor for PAH, suggest that a common receptor or pathway may exist. Like fenfluramine, amphetamines are "substrate-type" releasers,14 increasing neurotransmitter release via substrate-mediated exchange and through disruption of intracytoplasmic storage vesicles. Fenfluramine is specific for the serotonin transporter protein, while methamphetamine and amphetamine act more potently on norepinephrine and dopamine transporters with modest activity on the serotonin transporter15 (Fig 2 ).


Figure 2
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  		Figure 2.. Although all three molecules are structurally similar, amphetamine and methamphetamine are more potent releasers of dopamine and norepinephrine and relatively weak releasers of serotonin, while fenfluramine acts mainly on serotonin release.15

 
Serotonin and norepinephrine have both been proposed as potential contributors to the development of pulmonary hypertension. Both have vasoconstrictive and growth modulating effects on smooth-muscle cells, and their transporters are present in the pulmonary vasculature.1617181920 The serotonin transporter itself may also be important, as levels of this transporter are increased in idiopathic PAH, its overexpression in mice leads to modest increases in right ventricular systolic pressures, and serotonin transporter antagonists can block serotonin-mediated smooth-muscle cell growth in vitro.2122

If an association between stimulants and PAH exists, it will be important to determine whether only certain stimulants are associated or whether it is a class effect. In this study, only 2 patients with idiopathic PAH reported prescription amphetamine use, compared with 1 patient reporting illicit amphetamine use, 24 patients reporting illicit methamphetamine use, and 1 patient reporting illicit cocaine use. The majority of illicit methamphetamine users in national surveys report either inhaling or smoking the drug2324; this direct exposure of drug to the pulmonary vasculature may also be an important determinant of overall risk.

The high rate of stimulant use among the nine (excluded) HIV patients with PAH is also intriguing: HIV infection is considered to be a "definite" PAH risk factor,25 but how HIV leads to pulmonary hypertension remains unclear, as neither CD4 count or viral load have correlated well with the development of PAH.26 Higher-than-expected rates of IV drug use have been reported in some series,27 but rates of non-IV stimulant use have not been described.

Higher rates of use might have been expected among patients with PAH associated with known risk factors compared with patients with CTEPH, based on pathophysiology in these forms of PAH that is presumably more similar to idiopathic PAH than CTEPH. It is unclear whether the lack of this finding relates to a true lack of added risk vs limitations in study design.

In summary, this study found a significant association between stimulant use and idiopathic PAH, and suggests that stimulant use may be a risk factor for PAH. Though preliminary, these results are important because of the widespread and increasing use of both prescription and illicit stimulants. Additional study of a wider spectrum of stimulant drugs is warranted to more clearly define this risk, and particular focus on the HIV-associated PAH subgroup is needed to clarify the role of stimulant use in this patient population.

Acknowledgements

We thank Cindy Morgan, MS, and Fernando Torres, MD, for assistance in statistical analysis and manuscript preparation.

Footnotes

Abbreviations: CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension

The authors have no conflicts of interest to disclose.

Received for publication March 28, 2006. Accepted for publication May 27, 2006.

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R. B. Rothman and M. H. Baumann
Methamphetamine and Idiopathic Pulmonary Arterial Hypertension: Role of the Serotonin Transporter
Chest, October 1, 2007; 132(4): 1412 - 1413.
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