Overview of Methamphetamine-Associated Pulmonary Arterial Hypertension

Abstract

Topic Importance

The global surge in methamphetamine use is a critical public health concern, particularly due to its robust correlation with methamphetamine-associated pulmonary arterial hypertension (MA-PAH). This association raises urgent alarms about the potential escalation of MA-PAH incidence, posing a significant and imminent challenge to global public health.

Review Findings

This comprehensive review meticulously explores MA-PAH, offering insights into its epidemiology, pathophysiology, clinical presentation, diagnostic intricacies, and management strategies. The pathogenesis, yet to be fully described, involves complex molecular interactions, including alterations in serotonin signaling, reduced activity of carboxylesterase 1, oxidative stress, and dysregulation of pulmonary vasoconstrictors and vasodilators. These processes culminate in the structural remodeling of the pulmonary vasculature, resulting in pulmonary arterial hypertension. MA-PAH exhibits a more severe clinical profile in functional class and hemodynamics compared with idiopathic pulmonary arterial hypertension. Management involves a multifaceted approach, integrating pulmonary vasodilators, cessation of methamphetamine use, and implementing social and rehabilitation programs. These measures aim to enhance patient outcomes and detect potential relapses for timely intervention.

Summary

This review consolidates our understanding of MA-PAH, pinpointing knowledge gaps for future studies. Addressing these gaps is crucial for advancing diagnostic accuracy, unraveling mechanisms, and optimizing treatment for MA-PAH, thereby addressing the evolving landscape of this complex health concern.

Methamphetamine (MA), a highly addictive stimulant, has long been recognized for its detrimental effects on both physical and mental health. Misuse of this substance has been implicated in a range of neurologic and cardiovascular toxicities. Some studies1, 2, 3, 4 showed an association with the development of pulmonary arterial hypertension (PAH); these studies were sufficient for the 1998 World Symposium on Pulmonary Hypertension to upgrade MA to a "definite association" with drug and toxin-associated PAH.⁵ However, our understanding of the pathophysiological mechanisms underlying MA-associated PAH (MA-PAH) and the specific characteristics of patients with MA-PAH, such as dose-response relations, disease severity, and prognosis, remains limited.

The growing popularity and availability of MA in many parts of the world have led to concerns about a potential surge in MA-PAH cases. With the anticipated rise in MA use among individuals who use drugs, the incidence of this condition is expected to escalate in parallel. In light of these challenges, conducting a comprehensive review of the existing body of knowledge on MA-PAH was crucial. This review consolidates and synthesizes the available data, serving as a foundation for future research endeavors aimed at gaining a deeper understanding of MA-PAH. This review has several key objectives. First, it describes the state of our understanding of the pathogenesis of MA-PAH, especially related to potential targets for therapeutic interventions. Second, it describes what is known about the clinical presentation of MA-PAH, such as demographic factors and comorbidities, prognosis, and long-term outcomes of patients with MA-PAH. This understanding of the natural progression of the disease and its impact on the quality of life will be instrumental in developing effective management strategies. Lastly, the review describes an approach to treatment for MA-PAH.

By addressing this topic, we aim to pave the way for future research and evidence-based treatment and management strategies to effectively combat this alarming public health issue.

MA and Epidemiology of MA Use

MA, a dangerous psychomotor stimulant, exerts its effects by enhancing the signaling of catecholamines such as dopamine and norepinephrine. This is achieved through blocking catecholamine transporters, reversal of the catecholamine transporters, and inhibition of catecholamine catabolizing enzymes, resulting in increased catecholamine concentrations in both the central and peripheral nervous systems. However, this heightened adrenergic activity is accompanied by neurotoxicity and neuroinflammation, leading to neuronal cell death. Beyond its detrimental effects on the nervous system, MA use has also been implicated in the damage of various other organ systems, especially the cardiovascular system. This includes toxicities such as myocardial infarction, cardiomyopathy, and pulmonary hypertension (PH).⁶

Since the 1960s, MA misuse has emerged as a significant public health concern. The World Drug Report 2021 highlights that in 2019, an estimated 27 million individuals worldwide, equivalent to 0.5% of the global population, reported using amphetamine-type stimulants. This places MA as the third most commonly misused drug, following cannabis (used by 200 million individuals) and opioids (used by 62 million individuals). The prevalence of MA misuse varies across the globe, with North America exhibiting the highest rates at 2.3%, and Africa reporting the lowest rates at 0.4%. Global data provided by the US Drug Enforcement Administration⁷ further show the increasing popularity of MA. The number of countries reporting seizures of MA samples rose has risen from 79 (2005-2009) to 111 (2015-2019). Moreover, global seizures of MA increased by 64% between 2018 and 2019 alone.⁸ It is worth noting that the purity and potency of seized MA samples often exceed 90%,⁷ while manufacturing costs have decreased. These factors, coupled with the ease of access, likely contribute to the rising trend of MA misuse observed worldwide.

In the United States, MA usage varies by region, with higher rates in Western states compared with the East; since 1990, MA use has tended to spread across the country.⁹ The higher occurrence of MA use in Western states has been associated with more MA laboratories in the region, contributing to a sustained presence of the drug. Simultaneously, major production facilities, termed “superlabs,” emerged in Southern California and Northern Mexico, producing significantly larger amounts of MA. Mexican drug trafficking groups facilitated the distribution of this MA from these superlabs to key hubs in the West and Midwest. This increased supply resulted in the widespread availability of substantial quantities of affordable MA throughout these areas.¹⁰

MA can be administered through a variety of routes, including smoking, snorting, injecting, and oral ingestion. Interestingly, the preferred route of MA administration varies between sexes. It has been observed that male individuals tend to favor injection or snorting, whereas female individuals are more inclined toward smoking as their preferred method.¹¹ In contrast to some other illicit substances in which there is a significant disparity between the sexes, the patterns of MA dependence treatment reveal a greater equality between the sexes: nearly an equal number of female individuals seek treatment for MA dependence as males, highlighting that MA addiction affects both sexes to a similar extent.¹²

The misuse of psychostimulants, particularly MA, has had devastating consequences in terms of overdose deaths. In 2020 alone, approximately 24,000 individuals died of drug overdoses involving psychostimulants other than cocaine, with MA being the primary culprit.¹³ The financial impact of MA misuse is also substantial: annual hospital costs associated with amphetamine misuse rose significantly, from $436 million in 2003 to $2.17 billion by 2015, reflecting the growing burden on health care systems.¹⁴ Moreover, the total direct and indirect economic costs of MA misuse were estimated to exceed $23.4 billion in 2005, including health care expenses, loss of productivity, and legal and criminal justice costs.

Pulmonary Arterial Hypertension and Its Association With MA

PH is a hemodynamic condition now defined by a mean pulmonary artery pressure > 20 mmHg.¹⁵ PH is classified into five groups, each with a distinct pathobiology. Group 1, known as PAH, is characterized by histopathologic changes generally consistent across cases, irrespective of associated conditions or risk factors. These changes primarily involve pulmonary vascular remodeling and proliferation within the small- to medium-sized pulmonary arterioles, including endothelial cell proliferation, smooth muscle hypertrophy, and the loss/obliteration of precapillary arterioles. In addition, there are changes in the pulmonary arteriolar walls, such as concentric or eccentric laminar lesions, neointimal formation, fibrinoid necrosis, in situ thrombi, and the formation of complex lesions known as “plexiform lesions.” Although the precise pathogenic mechanisms driving the development of PAH are not yet fully understood, genetic and environmental factors have been implicated in the aberrant behavior of smooth muscle and endothelial cells, maladaptive inflammatory responses, and disruptions in vasodilator and vasoconstrictor signaling pathways.¹⁶

Our understanding of PAH began with its initial description in 1891 by Romberg, who observed pulmonary vascular pathologic changes during autopsies.^17,18 However, it was not until 1951 that David Dresdale provided a description of a hemodynamic profile of PH without an apparent cause, naming it “primary pulmonary hypertension.” Despite this, PAH did not gain significant attention within the medical community until the late 1960s when a surge of new cases emerged in association with the use of aminorex fumarate in Switzerland, Germany, and Austria. This epidemic prompted the World Health Organization (WHO) to convene its first meeting in Geneva in 1973, resulting in the publication of the inaugural consensus report. Subsequently, in 1998, during the Second World Symposium on Pulmonary Hypertension, a classification of PH was established to distinguish various PH categories based on shared pathologic findings, hemodynamic characteristics, and management approach.^19,20

The development of PAH/WHO Group 1 PH, pulmonary vascular remodeling/proliferation that increases pulmonary vascular resistance and, if untreated, ultimately results in right-sided heart failure and death, has been associated with various drugs and toxins. These substances include appetite suppressants such as aminorex and fenfluramine/phentermine (fen-phen), stimulant drugs such as cocaine or amphetamines, and nonstimulant US Food and Drug Administration-approved therapies such as dasatinib. Consequently, drug- or toxin-induced PAH is classified as WHO Group 1.3 (Drug and Toxin-induced PAH).⁵

The potential association between MA exposure and PAH first surfaced in a 1993 case report detailing severe PAH in a truck driver with a 10-year history of MA and propylhexedrine inhalation.²¹ Since then, an accumulating body of evidence has further substantiated this link. In a retrospective cohort study, it was discovered that patients with idiopathic PAH (IPAH) were 10 times more likely to have a history of use of stimulants, including MA, cocaine, or amphetamines (with MA being the most prevalent), compared with individuals with PAH associated with known risk factors. This association was also approximately eight times higher compared with patients with chronic thromboembolic PH.¹ In 2017, Zamanian et al,² using International Classification of Diseases, Ninth Revision (ICD-9), codes in a Healthcare Cost and Utilization Project database from California, observed a higher risk of PAH-related hospitalizations among individuals who used MA, compared with individuals who did not use MA (relative risk [RR], 2.64; 95% CI, 2.18-3.2). Based on the growing evidence, MA was upgraded from a “likely” to a “definite” risk factor for PAH at the 2018 World Symposium on Pulmonary Hypertension.⁵

Epidemiology of PAH in Individuals Who Use MA

According to the French Registry, drug- or toxin-induced PAH accounts for approximately 9.5% of all PAH cases.²² Similarly, Group 1.3 was approximately 10.5% of reported cases in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).²³ However, there has been no study providing precise epidemiologic data on MA-PAH. Drew et al²⁴ used urine toxicology testing for MA and ICD-9 diagnosis for PH in an electronic medical record database; they observed a cumulative incidence of PH of approximately six of every 1,000 patients testing positive for MA, with an overall prevalence of 9.77 of every 1,000 patients testing positive for MA. Zamanian et al,² using California hospitalization data from Healthcare Cost and Utilization Project data sets covering the period between 2005 and 2011, estimated the incidence of likely PAH-related hospitalizations to be 373.2 cases per million individuals who did not use MA; among inidividuals who did use MA, the incidence significantly increased to 984.6 cases per million (RR, 2.64). The reports have both geographic and methodologic limitations, and the exact incidence and prevalence of PAH in individuals who use MA remain unknown and warrant further investigation.

Not surprisingly, the geographic distribution of MA-PAH tends to track MA use, at least in the United States. Kolaitis et al³ identified a higher prevalence of MA-PAH in the Western states of the United States. This observation is likely explained by the elevated prevalence of MA use in these regions, as previously discussed in detail in the “MA and Epidemiology of MA Use” section.

One of the challenges in understanding the incidence and prevalence of MA-PAH was the lack of clarity regarding the dose-response relationship between the intensity/duration of MA exposure and the risk of development or severity of MA-PAH, which contributes to an absence of clear diagnostic criteria for MA-PAH. A previous retrospective study approached the definition of MA-PAH by identifying patients with PAH who had a significant history of MA exposure, specifically defined as using the substance more than three times a week for a period exceeding 3 months.² The criteria utilized by the author² to identify patients with MA-PAH were based on a case-control study conducted in 1996.²⁵ This study assessed the risk of primary PH/WHO Group 1 and reported an OR of 23.1 for developing primary PH/Group 1 in individuals using appetite suppressant agents (mainly derivatives of fenfluramine) for > 3 months, compared with an OR of only 1.8 in those who used them for < 3 months. These findings suggested that a duration of 3 months was a signification exposure indicator.²⁵ However, it is important to note that this study focused on patients with a history of exposure to derivatives of fenfluramine. Although both substances (methamphetamine and fenfluramine) can affect serotonin levels to some extent, they possess distinct chemical structures. Consequently, there is a limitation in generalizing the study's findings to the MA-PAH population.

In an effort to bridge the knowledge gap, the Screening of Pulmonary Hypertension in Methamphetamine Abusers (SOPHMA) study,²⁶ based in Hong Kong, was designed to provide additional insights into the epidemiology of MA-PAH. This multicenter study plans to enroll 400 patients with MA use disorder who report MA use in the last 2 years, and it will obtain demographic information, detailed drug use history, and cardiovascular risk factors and diseases. The study will also screen for PH using echocardiography, with a re-screen of participants with a low probability of PH within 1 year. Participants with a moderate or high probability of PH according to echocardiography will undergo right heart catheterization to better characterize their hemodynamics. The study aims to develop a prediction model specifically tailored for identifying PAH in individuals who use MA. However, the study is currently suspended due to the impact of COVID-19 pandemic on recruitment.

Similarly, the National Institutes of Health-funded Exposure to Substances in PAH (XPOSE-PAH) study (1R01HL159886)²⁷ in the United States is a multicenter case-control investigation aimed at deepening our understanding of MA-PAH epidemiology. Its objectives encompass identifying risk factors for clinical deterioration in MA-PAH compared with IPAH. The study also seeks to explore whether the association between MA and PAH is influenced by genetic variants or the activity of carboxylesterase 1 (CES1), discussed in further detail in the “Proposed Pathogenic Mechanisms of MA-PAH and the Impact of Sex on Disease” section. Both initiatives collectively hold the potential to offer insights into the incidence, prevalence, pathogenesis, and diagnostic approaches related to MA-PAH.

Characteristics and Clinical Course of MA-PAH

As subdivisions of WHO Group 1 PH, both MA-PAH and IPAH are characterized by precapillary PH. The majority of data on MA-PAH stem from two notable studies (Table 1), suggesting significant clinical and physiologic distinctions. Zamanian et al² compared 90 patients with MA-PAH and 97 patients with IPAH at the Stanford University Pulmonary Hypertension Program between 2003 and 2015, on clinical characteristics, hemodynamics, histopathologic findings, and outcomes data between the two groups. Kolaitis et al³ used the Pulmonary Hypertension Association Registry (PHAR), a US patient registry enrolling patients from Pulmonary Hypertension Care Centers; they compared 118 patients with MA-PAH and 423 patients with IPAH on demographic characteristics, regional distribution in the United States, hemodynamics, health-related quality of life (HRQOL), PAH-specific treatment, and health care use between MA-PAH and IPAH. These two studies provided valuable, if numerically limited, insights into the unique features of MA-PAH (Table 2).

Table 1.

Summary of Two Studies

Study Details	Zamanian et al2	Kolaitis et al3
Population	Patients with MA-PAH presented to the Stanford University Pulmonary Hypertension Program between 2003 and 2015	Patients with MA-PAH from PHAR cohort
Method	A prospective cohort study comparing demographic characteristics, clinical presentation, hemodynamics, histopathology, and outcome between 90 patients with MA-PAH and 97 patients with IPAH	A prospective cohort comparing demographic characteristics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use between 118 patients with MA-PAH and 423 patients with IPAH
Diagnostic criteria of MA-PAH	Inclusion: meet criteria for PAH by diagnostic RHC with significant exposure of (meth)amphetamine, defined by ≥ 3 episodes of use per week for > 3 months Exclusion: patients with other causes of PH such as left ventricular dysfunction, valvular heart disease, chronic thromboembolic disease, or use of concomitant anorexigens and nonamphetamine illicit substance use, such as cocaine	The diagnosis and the etiology of PH were determined by the enrolling PHAR center, as part of standard clinical practice No central guidelines were provided to PHAR investigators quantifying sufficient exposure to MA necessary to make a diagnosis of MA-PAH
Outcome	Five-y and 10-y event-free survival rates of 47.2% and 25% in MA-PAH compared with 64.5% and 45.7% in IPAHa Increased risk of an eventa with hazard ratio of 1.66 (2.04 in the multivariate model), compared with IPAH	Survival was similar between groups (hazard ratio for death, 1.07)b No difference in the rate of referral for lung transplantation Patients with MA-PAH were more likely to be seen in the ED and more likely to be hospitalized, compared with participants with IPAH

IPAH = idiopathic pulmonary arterial hypertension; MA = methphetamine; MA-PAH = methamphetamine-associated pulmonary arterial hypertension; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PHAR = Pulmonary Hypertension Association Registry; RHC = right heart catheterization.

^aDeath, transplantation, or hospitalization for right ventricular failure were considered events.

^bNote that the PHAR, being relatively young and having few deaths, may reveal more pronounced differences in survival rates as it matures.

Table 2.

Consensus Findings From Zamanian et al² and Kolaitis et al³ in the Comparison of MA-PAH and IPAH Patients

Patient Characteristics	MA-PAH	IPAH
Age, y	Younger; mid 40s	Older; 40s to 50s
Female	∼60%	∼70%-80%
White, non-Hispanic	> 70%	50%-70%
Patient with advanced WHO functional class (3 and 4)	Higher; 60%-90%	Lower; 55%-70%
Hemodynamics from RHC	Less favorable with higher PVR, lower cardiac output, and SVI	More favorable with lower PVR, higher cardiac output, and SVI

IPAH = idiopathic pulmonary arterial hypertension; MA-PAH = methamphetamine-associated pulmonary arterial hypertension; PVR = pulmonary vascular resistance; RHC = right heart catheterization; SVI = stoke volume index; WHO = World Health Organization.

Clinical Characteristics and Socioeconomic Factors: A Comparison Between Patients With MA-PAH and Patients With IPAH

Data from both cohorts revealed distinct clinical characteristics in patients with MA-PAH compared vs those with IPAH. Patients with MA-PAH had a median duration of continuous MA exposure of 60 months, consistent across both sexes (72 months for male participants and 60 months for female participants; P > .5). A majority of individuals who use MA (70%) reported daily use, primarily through inhalation or smoking. Patients with MA-PAH tend to be younger, typically in their early to mid-40s, while IPAH patients were about 5 years older on average. The time from the onset of symptoms to diagnosis was similar between the two groups, with a median of 11 months in patients with MA-PAH and 10 months for patients with IPAH. Notably, both MA-PAH and IPAH exhibited a female predominance, although the proportion of female participants was lower in MA-PAH (approximately 60%) compared with IPAH (approximately 80%). In addition, the majority of patients in both groups were non-Hispanic White, with similar anthropometric measures and comorbidities. The data from our recent report, drawn from the PAH Biobank (a multi-center, National Institutes of Health-sponsored, observational study), support and correspond with the earlier observations regarding age at diagnosis, sex distribution, and ethnic predominance.²⁸

Within the PHAR cohort, the MA-PAH group consistently reported lower scores in generic mental HRQOL and PAH-specific HRQOL compared with the IPAH group, both at baseline and during subsequent visits, compared with the IPAH group. However, psychosocial challenges of substance use disorder may contribute to this, and it may not be related to direct neurotoxicity. Interestingly, the MA-PAH group reported better generic physical HRQOL compared with the IPAH group. However, in adjusted models, patients with MA-PAH still exhibited worse generic mental HRQOL and PAH-specific HRQOL, whereas the association between MA-PAH and better generic physical HRQOL did not persist.

In terms of socioeconomic factors, findings were mixed. In the Stanford cohort, patients with MA-PAH had a higher median household income of $67,295 compared with patients with IPAH (median household income, $61,228), although this difference did not reach statistical significance. However, in the PHAR group, patients with MA-PAH exhibited lower socioeconomic status, as indicated by a lower rate of insured patients, a smaller proportion of college graduates, a lower employment rate, and lower taxable income per year.

Physiologic and Hemodynamic Findings in Patients With MA-PAH Compared With Patients With IPAH Patients

In both cohorts, although patients with MA-PAH exhibited a lower WHO functional class, no statistically significant difference was observed in the 6 min walk distance between patients with MA-PAH and those with IPAH. Data from the Stanford cohort revealed that patients with MA-PAH displayed a lower 2 min heart rate recovery, implying reduced physical fitness and exercise capacity in MA-PAH.

Consistent with these findings, patients with MA-PAH exhibited less favorable right-sided heart hemodynamics compared with patients with IPAH. Echocardiography in the Stanford cohort revealed that patients with MA-PAH were more likely to have dilated right atrium, moderate to severe right ventricular (RV) dilation, and dysfunction. These findings were consistent with diagnostic right heart catheterization data from both cohorts, indicating evidence of more severe RV overload in MA-PAH, characterized by higher right atrial pressures. The hemodynamic profile of MA-PAH tended to be more concerning, with higher pulmonary vascular resistance, lower cardiac output, and a reduced stroke volume index. It is worth noting that although these differences did not consistently reach statistical significance, they collectively suggested a more challenging hemodynamic situation in MA-PAH. Nonetheless, our recent study, analyzing data from the PAH Biobank, did not reveal any statistically significant differences in hemodynamics between MA-PAH and IPAH. The lack of statistical significance may be attributed to insufficient statistical power stemming from a small sample size. This underscores the imperative for additional research to validate and strengthen these findings.²⁸

MA is known to have a variety of effects on the cardiovascular system, including on the systemic circulation and the left side of the heart.²⁹ As some of these effects can influence left atrial pressures and contribute to postcapillary PH, it is important to consider whether this may be contributing to any rise in pulmonary artery pressures in an individual patient, and a different WHO category may be a more appropriate diagnosis. Interestingly, echocardiography data from the Stanford cohort did not indicate any statistically significant differences in left-sided hemodynamics; including left atrial size, left ventricular morphology, size, or function between individuals with MA-PAH and those with IPAH. It is possible that patients with MA-PAH with left ventricular dysfunction might be excluded automatically based on PAH criteria, placing them under PH Group 2. Given that previous studies have reported cardiomyopathy-associated MA,^4,30 it is crucial to assess its potential impact on the left side of the heart, even within the PAH population. Further investigation into the left-side cardiac function in patients with MA-PAH is necessary to ascertain whether it might contribute to adverse right-sided hemodynamics and the observed poorer functional status in patients with MA-PAH.

As for pulmonary function, data from the Stanford cohort indicated that spirometry results remained generally preserved and comparable in both groups. The exception was the percent predicted diffusion capacity, which was higher in MA-PAH.

Radiologic and Pathologic Findings in MA-PAH With MA-PAH Compared With Patients With IPAH

The data in this area were derived from the Stanford cohort. Pulmonary artery angiography performed on patients with MA-PAH revealed radiologic findings consistent with those observed in patients with IPAH. These findings included rapid tapering, monopedal vascular dropout, and a loss of capillary blush. These radiologic features suggest compromised blood flow within the pulmonary arteries.

Histopathologic examination of lung parenchyma samples from patients with MA-PAH exhibited similar pathologic changes as seen in IPAH. These changes included the presence of plexiform lesions, which are abnormal formations of small blood vessels, as well as proliferative capillaries in the pulmonary interstitium, intimal fibrosis, and medial hypertrophy. These pathologic alterations reflect the remodeling and narrowing of the pulmonary arteries, contributing to increased pulmonary vascular resistance. In addition to the typical histopathologic changes of PAH, the presence of foreign material used to “cut” illicit drugs may contribute to vascular obstruction.² Although not described specifically in MA-PAH, these foreign bodies may also elicit an inflammatory response driven by macrophages and multi-nucleated giant cells, so-called “foreign body granulomas” that also contribute to the rise in pulmonary vascular resistance; this, for instance, was described in an autopsy series of individuals who use drugs, 20% of whom tested positive for MA.³¹

The radiologic and pathologic findings in MA-PAH parallel those observed in IPAH, suggesting a shared underlying pathophysiology and vascular remodeling in both conditions.

Treatments and Outcomes of Patients With MA-PAH Compared With Patients With IPAH

In terms of treatment, there was no significant difference in the rate of patients receiving dual combination therapy between the MA-PAH and IPAH groups. However, patients with MA-PAH were less likely to be initiated on triple combination therapy or parenteral prostacyclin therapy in both the Stanford and PHAR cohorts, despite less favorable hemodynamics. Similarly, the time to initiation of IV or subcutaneous prostacyclin analogue therapy was longer in MA-PAH groups compared with IPAH patients in the Stanford cohort. These findings suggest that patients with MA-PAH may have received less aggressive or advanced treatment options compared with patients with IPAH.

In the Stanford cohort, both 5- and 10-year event-free (events comprised death, transplantation, or hospitalization for RV failure) survival rates were worse in patients with MA-PAH compared with patients with IPAH. The event-free survival rate at 5 years was 47.2% in MA-PAH compared with 64.5% in IPAH, and at 10 years it was 25% in MA-PAH compared with 45.7% in IPAH. Patients with MA-PAH had worse outcomes compared with patients with IPAH even following adjustment for confounding factors such as age, sex, race, socioeconomic status, and use of parenteral prostacyclin analogues. It is important to highlight that despite lower treatment adherence among patients with MA-PAH compared with patients with IPAH (46.7% vs 60.3%), this difference did not explain the poorer prognosis in the multivariable analysis.

However, the PHAR cohort found that there was no disparity in the rate of lung transplantation referral between the MA-PAH and IPAH groups, and no participants in the registry underwent lung transplantation. In addition, the overall survival rates were similar (hazard ratio for death, 1.07 [0.33-3.44]; P = .9). These observations might be attributed to the relatively young age of the registry, resulting in few recorded deaths. It is possible that distinctions in survival could become more evident as the registry matures.

Among individuals with cardiovascular complications resulting from MA use, the involvement of the right side of the circulation has been associated with worse outcomes. MA-PAH, characterized by higher RV systolic pressure and impaired RV function, displays unique features and endures more adverse outcomes when contrasted with individuals who use MA without developing PAH and those afflicted by MA-induced cardiomyopathy. In a study conducted by Zhao et al,⁴ at a median follow-up of 20 months, the MA-PAH group exhibited the highest all-cause mortality rate compared with both the individuals who used MA without PAH and the MA-induced cardiomyopathy group (18% vs 4.5% vs 15.2%, respectively; P < .001).

Proposed Pathogenic Mechanisms of MA-PAH and the Impact of Sex on Disease

Although MA is distributed throughout the body, its uptake is highest in the lungs following IV administration.³² This significant pulmonary exposure likely contributes to pulmonary toxicity and vascular damage, ultimately leading to the development of MA-PAH. Various mechanisms have been proposed as contributors to the pathogenesis of MA-PAH, including disturbances in serotonin signaling, oxidative stress, reduced activity of CES1, and dysregulation of pulmonary vasoconstrictors and vasodilators (Fig 1).

Figure 1.

Overview of proposed pathogenic mechanisms of MA-PAH with a modification by estrogen. Methamphetamine alters 5HT signaling, promotes oxidative stress, dysregulates vasoconstriction/vasodilators, and reduces CES1, leading to vasoconstriction and vascular remodeling associated with MA-PAH. 5-HT = serotonin; 16α-OHE1 = 16 alpha-hydroxy estrone; BMPR2 = bone remodeling associated with methamphetamine-associated pulmonary arterial hypertension; CES1 = carboxylesterase 1; CYP1B1 = cytochrome P450 1B1; eNOS = endothelial nitric oxide synthase; ERS = endoplasmic reticulum stress; MAO-A = monoamine oxidase A; MA-PAH = methamphetamine-associated pulmonary arterial hypertension; NO = nitric oxide; ROS = reactive oxygen species; SERT = serotonin transporter; TPH1 = tryptophan hydroxylase-1; TXA2 = thromboxane A₂. Created with BioRender.com.

The “estrogen paradox” in PAH refers to the intriguing observation that females are more susceptible to PAH but experience better clinical outcomes compared with males. Numerous PAH registries consistently report a higher prevalence of PAH in female participants, especially idiopathic and hereditary forms,^22,33,34 occurring at an earlier age compared with male participants. Female participants with PAH, however, also exhibit more favorable hemodynamic profiles and better responses to certain treatments, possibly influenced by the complex effects of estrogen on various pathways in the body. Animal models of PAH reinforce this paradox, showing that in various models, including chronic hypoxia-induced PH, monocrotaline-induced PH, and Sugen/hypoxia-induced PH, female animals tend to exhibit less severe responses to PAH-inducing factors compared with male animals. Notably, estrogen supplementation has been found to mitigate this vulnerability.35, 36, 37

Although extensive research has explored the estrogen paradox in other forms of PAH, data specifically focusing on PAH associated with MA use (MA-PAH) remain limited. Studies^2,3 have shown that MA-PAH is more prevalent in female participants, mirroring the pattern observed in IPAH. However, the proportion of female participants among patients with MA-PAH was lower, approximately 60% in MA-PAH compared with roughly 80% in IPAH. One potential explanation for this difference could be variations in the extent of exposure and the route of administration between sexes. These hypotheses are supported by previous studies, which found that among people who use MA, male participants had higher rates of MA usage compared with female participants³⁸ and preferred injection as their method of choice, whereas female participants tended to opt for smoking.¹¹

In addition, an analysis of the Healthcare Cost and Utilization Project database revealed that the risk of receiving an ICD-coded likely PAH diagnosis in hospitalized individuals who use MA was more pronounced in female participants, with an RR of 3.32 (95% CI, 2.56-4.29; P < .001), compared with male subjects (RR, 2.16; 95% CI, 1.6-2.9; P < 0.001).² These findings highlight the importance of considering sex differences in the development and progression of PAH associated with MA use.

Later in this discussion, we delve into the pathogenesis of MA-PAH and also explore how estrogen may influence the interconnected pathways involved in the development of MA-PAH. While the exact mechanisms remain incompletely understood, considering the potential effects of estrogen on these pathways provides valuable insights into the estrogen paradox in MA-PAH. Further research is needed to elucidate the specific interactions between estrogen and the pathogenic mechanisms of MA-PAH, which may offer new avenues for targeted therapies and improved management of this condition.

Alteration of Serotonin Signaling

Serotonin’s Role in PAH Pathophysiology

The role of serotonin in the pathogenesis of PAH was first recognized in the 1960s, based on epidemiologic studies with a higher incidence of PAH in patients using serotonin agonist drugs such as fenfluramine and phentermine.³⁹ Serotonin plays a role in vasoconstriction, proliferation, and remodeling of pulmonary artery smooth muscle cells (PASMCs) through several mechanisms. It activates serotonin receptors in PASMCs, resulting in vasoconstriction and an elevation in intracellular calcium levels, and mediates the proliferation of human PASMCs.40, 41, 42 In addition, serotonin can be internalized through the serotonin transporter (SERT), leading to transcriptional regulation by influencing histone-dependent epigenetic effects, ultimately contributing to the proliferation of PASMCs.^43,44 Furthermore, serotonin induces oxidative stress by generating reactive oxygen species (ROS). The generated ROS subsequently triggers the oxidation of protein tyrosine phosphatases, leading to the phosphorylation of downstream proteins, including mitogen-activated protein kinases, which contributes to the proliferation of human PASMCs.^45,46 ROS also facilitates nuclear translocation of ERK1/ERK2, which phosphorylates nuclear growth factors and induces mitogenesis and proliferation, as shown in animal studies.⁴⁷

Impact of MA on Serotonin and Its Implications in MA-PAH Pathogenesis

MA is believed to contribute to the development of MA-PAH by influencing serotonin levels and altering serotonin signaling. It achieves this by increasing serotonin synthesis, reducing serotonin metabolism, enhancing serotonin accumulation, and promoting serotonin release.

Studies have shown that MA, along with other SERT substrates such as fenfluramine and 3,4-methylenedioxymethamphetamine, can elevate serotonin levels by facilitating the SERT-mediated release of serotonin from platelets in a dose-dependent manner.⁴⁸ Within the lungs, MA exerts significant effects on serotonin concentration. It upregulates the expression of tryptophan hydroxylase-1, an enzyme crucial for serotonin synthesis, as well as the expression of SERT protein and vesicular monoamine transporter 2, which are involved in serotonin storage and release. Concurrently, MA downregulates the expression of monoamine oxidase A, an enzyme responsible for serotonin breakdown. These changes in gene expression and protein levels collectively contribute to the overall increase in serotonin concentration.

Furthermore, MA also increased the expression of 5-hydroxytryptamine receptor 1β (5-HT1β; serotonin receptor) and SERT in pulmonary arteries in a rat model. This effect was mitigated by fluoxetine, a selective serotonin reuptake inhibitors known to inhibit SERT. The observed increase in the expression of 5-HT1β and SERT was associated with an augmented medial wall thickness of pulmonary arteries.^49,50 These findings suggest that the dysregulation of serotonin signaling due to MA exposure plays a role in the development of MA-PAH.

The synergistic impact of serotonin and estrogen on PAH development, potentially extending to MA-PAH, hinges on the key role of the estrogen metabolite, 16 alpha-hydroxy estrone (16α-OHE1), generated by cytochrome P450 1B1.51, 52, 53 This metabolite exerts significant proinflammatory, pro-mitogenic, and pro-angiogenic effects, mediated by the enhanced production of ROS, leading to proliferation of PASMCs⁵⁴ and inhibiting bone morphogenetic protein receptor 2 and bone morphogenetic protein, which further contributes to PASMC proliferation in PAH.^55,56

Moreover, in a study involving mice, the administration of estradiol was found to result in elevated RV systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy, specifically in female mice overexpressing SERT. Notably, these effects were reversed upon ovariectomy but were reinstated with the chronic administration of estradiol.⁵⁷ In addition, another study in mice PASMCs found that elevated serotonin levels upregulated cytochrome P450 1B1,⁵⁸ leading to an increase in 16α-OHE1. Similarly, a study using human PASMCs found that estradiol upregulates the expression of tryptophan hydroxylase-1, 5-HT1β receptors, and SERT. Another study involving human PASMCs showed similar findings, with an increased expression of the 5-HT1β receptor in PASMCs derived from female participants with PAH.⁵⁹ These findings underscore the intricate interplay between serotonin and estrogen pathways in the pathogenesis of PAH.

Oxidative Stress

Although oxidative stress is known to play a significant role in the development of MA-induced neurotoxicity,^60,61 evidence also suggests that oxidative stress may contribute to the development of MA-PAH. Notably, the preclinical study revealed that amphetamine/MA leads to an increased production of mitochondrial ROS during hypoxia. Subsequently, these heightened ROS levels activate caspase-3, initiating the process of DNA damage within pulmonary artery endothelial cells. This cascade of events probably plays a pivotal role in the remodeling of pulmonary vasculature in MA-PAH.⁶²

In addition, experimental studies on rats have shown that MA-induced ROS stimulates endoplasmic reticulum stress, leading to an increase in caspase-12 levels and ultimately resulting in caspase-dependent cell apoptosis.⁶³

Estrogens can affect this pathway through the action of 16α-OHE1, an estrogen metabolite. This compound has been observed to enhance the production of ROS and plays a significant role in the development of PAH. It exerts marked proinflammatory, pro-mitogenic, and pro-angiogenic effects.⁵⁴

Reduction in the Activity of CES1

CES1 is a serine esterase, accounting for 80% to 95% of total hydrolytic activity in the liver. It plays a crucial role in metabolizing a wide range of drugs, especially the ester-prodrugs.⁶⁴ In humans, CES1 is primarily abundant in the liver, with lower expression in the lung and brain. Importantly, individuals carrying CES1 polymorphisms characterized by diminished enzymatic activity face an elevated susceptibility to drug-related toxicity primarily because of the accumulation of specific substances.⁶⁵

Orcholski et al⁶⁶ reported differential CES1 expression in the lungs of healthy individuals and those with MA-PAH using immunofluorescence studies, with CES1 expression notably diminished or absent in the remodeled vessels of all four patients with MA-PAH compared with samples from healthy individuals. Furthermore, the authors conducted a whole-exome sequencing analysis in patients with MA-PAH and IPAH. They observed that the rs115629050 variant of CES1 was exclusively present in patients with MA-PAH. Notably, their investigation revealed a substantial reduction in CES1 activity in patients with MA-PAH carrying the CES1 rs115629050 single nucleotide variant, compared with healthy donors. This decreased CES1 activity correlated with an increased vulnerability to MA-induced apoptosis, a consequence of elevated ROS production and disrupted autophagy flux. Interestingly, the author emphasizes that MA lacks ester bonds, making it improbable to function as a substrate for CES1. Although CES1 is not directly implicated in the metabolism of MA, its involvement may be critical in mitigating the formation of toxic metabolites arising from MA metabolism. Another study⁶⁷ referenced by the authors suggests that MA induces metabolite production in the brain, indicating the potential for MA to initiate the generation of ester or amide-containing toxic metabolites in pulmonary endothelial cells. Further investigation is essential to explore and clarify this possibility. Consequently, the accumulation of these toxic esters or amides may lead to mitochondrial and endoplasmic reticulum dysfunction, resulting in endothelial damage.

Estrogen may potentially affect MA-PAH by modulating CES1 expression. A preclinical study⁶⁸ suggests that the administration of 17β-estradiol has a significant effect on CES1 and carboxylesterase 2 (CES2). More specifically, treatment with 17β-estradiol has been shown to decrease both the messenger RNA and protein levels of CES1 and CES2 in mouse and human hepatocytes. Interestingly, ovariectomized female mice displayed higher expression of CES1 and CES2 compared with control mice, and this elevation was reversed upon administration of 17β-estradiol. These findings provide further support for the idea that estrogen likely plays a regulatory role in the CES1 pathway, thereby potentially influencing the development and progression of MA-PAH.

Dysregulation of Pulmonary Vasoconstrictors and Vasodilators

MA has been implicated in the dysregulation of a number of mediators of vascular tone, including endothelin, nitric oxide (NO), and prostacyclin, contributing to the development of PAH. Studies in rats have shown that MA stimulates the release of endothelin-1, leading to vasoconstriction. This effect can be reduced by using an endothelin receptor antagonist, suggesting the involvement of an endothelin-dependent pathway mediated by the endothelin receptor.⁶⁹ In addition, MA seems to disrupt NO-mediated vasodilation, impairing NO signaling and reducing vasodilatory function in individuals who use MA.⁷⁰ Furthermore, MA generates ROS, which upregulates pulmonary vasoconstrictors such as endothelin-1 and thromboxane A₂, while attenuating levels of vasodilators such as prostacyclin.⁷¹ These findings show how MA may disrupt the balance between vasoconstrictors and vasodilators, ultimately contributing to the development of PAH.

Estrogen may modulate the risk of developing PAH through the NO and endothelin pathways. In terms of the NO pathway, estrogen seems to influence this pathway by activating endothelial nitric oxide synthase through the phosphoinositide-3 kinase-dependent pathway.^72,73 Notably, studies have reported higher levels of NO synthesis in female participants compared with male participants.⁷⁴ In animal models, the deletion of the endothelial nitric oxide synthase gene has been observed to have a more pronounced impact on pulmonary circulation in male mice than in female mice.⁷⁵ In addition, NO synthase inhibition had a greater effect on reducing bradykinin-induced vasorelaxation in small pulmonary arteries of male swine compared with female swine.⁷⁶ In line with these observations, a study involving humans with PAH revealed that male participants treated with a phosphodiesterase 5 inhibitor (PDE5I) were more likely to exhibit significant improvements in exercise capacity and HRQOL compared with female participants.⁷⁷ These sex differences in response to PDE5Is may be attributed to lower NO levels and cyclic 3′,5′ guanosine monophosphate in men, which can be enhanced by the increased availability of 3′,5′ guanosine monophosphate after PDE5I administration. In addition, differences in endogenous phosphodiesterase 5 levels between male and female participants may contribute to the varying responses to PDE5Is. These findings highlight the potential role of estrogen in modulating NO-mediated vasorelaxation and the interplay between NO signaling, estrogen levels, and the estrogen paradox in MA-PAH warrants further investigation.

The endothelin pathway may be influenced by estrogen, particularly through 2-methoxyestradiol, which is a potent metabolite of estradiol. 2-methoxyestradiol was shown to inhibit the synthesis of endothelin in endothelial cells.⁷⁸ In rat models, it has been shown that administering 2-methoxyestradiol along with endothelin receptor antagonists (ERAs) can reduce the severity of monocrotaline-induced PH.⁷⁹ Furthermore, in human studies, endothelin levels have been observed to be higher in men compared with women.⁸⁰ This aligns with the observation that women tend to have better responses to ERA treatments, as indicated by increased 6-min walk distance.⁸¹ These findings suggest that estrogen’s influence on endothelin and related pathways may contribute to the estrogen paradox observed in MA-PAH.

Practical Management of MA-PAH

Currently, there are no treatment guidelines specific to patients with MA-PAH and, as a result, patients with MA-PAH should be generally managed similarly to PAH patients with other etiologies.¹⁵ There are, however, some unique challenges to the management of MA-PAH.

At diagnosis, all patients with MA-PAH should undergo an initial risk assessment. Those in the low- or intermediate-risk groups should start on a combination of ERA and PDE5I. High-risk patients should initiate IV or subcutaneous prostacyclin analogues in addition to ERA and PDE5I. During follow-up, for patients in the intermediate-low risk group, adding a prostacyclin receptor agonist or switching PDE5I to a soluble guanylate cyclase stimulator is recommended. For those in the intermediate-high or high-risk groups, IV or subcutaneous prostacyclin analogues should be added.¹⁵

Common concerns that make physicians reluctant to start parenteral PAH therapy in patients with MA-PAH include the potential risk of IV access misuse and line infection. Prior studies^2,3 have indicated that patients with MA-PAH may be less likely to receive proper treatment, including triple combination therapy or parenteral prostacyclin therapy. Because patients with MA-PAH already have a poorer prognosis compared with those with IPAH,² the underutilization of parenteral therapy further hampers outcomes in this subgroup.

Data are lacking regarding line safety or complications in these MA-PAH populations; there may be lessons, however, from a potentially analogous patient population such as patients with HIV and end-stage renal disease. A history of IV drug use was not an independent predictor for access removal due to infection with adjusted hazard ratio of 0.96 (0.47, 1.96; P = not significant).⁸² Similarly, but perhaps less relevant, patients with end-stage renal disease undergoing arteriovenous access creation had no significant differences in 1-year access infection-free survival or all-cause mortality at 30 days or 1 year between patients with or without a history of IV drug use.⁸³ As a result, a history of IV drug use may not be a contraindication to IV PAH therapy in patients with MA-PAH. Alternatively, it may be worth considering subcutaneous forms of medication as a preferred route for high-risk patients with MA-PAH instead of IV administration.

Ensuring that individuals who use MA adhere to their PAH treatment presents added challenges. Research involving young men from sexual minority groups and transgender women living with HIV found that amphetamine/MA indirectly affected viral loads due to its negative association with adherence to antiretroviral therapy.⁸⁴ In addition, a study among men who have sex with men living with HIV indicated that MA use in the 3 months prior was significantly linked to a higher risk of nonadherence to antiretroviral therapy, with an adjusted OR of 3.08, compared with the group that did not use MA.⁸⁵ To tackle this challenge, a comprehensive approach should be adopted, encompassing the implementation of a patient education program and the promotion of a robust support network involving family, friends, or support groups. Furthermore, as described in a study involving individuals who use MA with HIV infection, there might be a role for telemedicine, which has shown promise in enhancing medication adherence. ⁸⁶ This study used individualized texting for adherence-building intervention and monitored antiretroviral therapy adherence using medication event monitoring system caps. The findings suggest that this approach is both feasible and well received for improving medication adherence.

Although there may be a lack of conclusive data to firmly establish whether abstaining from MA use can result in improved PAH outcomes or potential reversal of the condition, it remains a reasonable decision for patients to discontinue MA use. This rationale is supported by a case report in which MA-induced cardiomyopathy was reversed following MA abstinence.⁸⁷ Abstinence from MA can prevent disease progression in the context of PAH and diminish the risk of complications stemming from MA toxicity, such as cardiomyopathy and neurotoxicity. Therefore, incorporating and maintaining MA abstinence should be a fundamental component of the management plan for MA-PAH.

The comprehensive care of patients with MA-PAH should include care for the underlying etiology, namely the drug addiction. It is critical to involve the expertise of addiction medicine specialists who can contribute valuable insights and strategies for addressing the complex nature of addiction intertwined with MA-PAH. In addition, it is important to understand the context of the patient’s illnesses, and social workers can assess the broader social context of patients with MA-PAH, identifying potential stressors, support systems, and resources. They play a key role in connecting patients with rehabilitation programs and other community resources that can significantly contribute to the overall well-being of individuals dealing with MA-PAH.

A drug testing program should also be a part of the care of the MA-PAH patient. Monitoring through urine toxicology tests allows health care providers to promptly detect any signs of substance relapse; early identification provides an opportunity for timely intervention, support, and adjustments to the treatment plan, aiming to prevent further harm and promote sustained recovery. It is not currently possible to offer evidence-based recommendations on the nature (random vs scheduled) or frequency of a screening program as there are no data in this subset of patients and inconsistent experience in other settings.⁸⁸

Because there are no absolute contraindications to lung or heart-lung transplantation in the abstinent patient with MA-PAH, these patients should be referred to an appropriate center in accordance with current guidelines⁸⁹; criteria generally include patients at high risk despite appropriate therapy, high-risk variants, secondary organ dysfunction, and need for IV/subcutaneous prostacyclin therapy. There are, however, potential challenges and barriers to consider in this process. Concerns may arise about the adequacy of support systems, lack of insurance coverage, and financial difficulties. In addition, the presence of concomitant psychiatric disorders and polysubstance use can complicate the transplant evaluation process. These considerations underscore the importance of a multidisciplinary approach, involving addiction medicine specialists and social workers early in the care of patients with MA-PAH. Addressing and overcoming these obstacles is crucial to ensure that eligible patients with MA-PAH have access to transplant options and the necessary support for a successful outcome.

Future Directions

Moving forward, critical questions surround MA-PAH, requiring further investigation. Comprehensive epidemiologic data and identification of risk factors of MA-PAH are essential, and the ongoing XPOSE PAH study (1R01HL159886)²⁷ is expected to provide valuable insights. Understanding the potential synergistic effect of MA use with other forms of PAH, especially HIV-related PAH, is crucial. Research⁹⁰ indicates a higher incidence of individuals who use MA among patients with HIV-related PAH, prompting exploration of how HIV infection and MA use influence clinical characteristics and outcomes in affected individuals. In-depth exploration of potential synergistic effects can offer valuable insights into the mechanisms driving the increased incidence of PAH in this particular subgroup, and it may aid in identifying factors that influence disease severity and prognosis. Investigating the potential reversibility of MA-PAH upon cessation of MA use is vital for treatment decisions and patient outcomes. Identifying optimal therapeutic approaches and suitable monitoring methods for patients with MA-PAH will improve management and outcomes. Addressing these questions would advance our understanding of MA-PAH and enhance patient care.

Conclusions

The prevalence of MA misuse is significant worldwide, affecting both men and women. This highly addictive substance has been associated with toxic effects on various organs, including the lungs, and is considered a definite risk factor for the development of PAH. Studies have revealed that patients with MA-PAH, despite being younger, often exhibit more advanced disease with a higher functional class and lower cardiac index compared with patients with IPAH. Interestingly, similar to other forms of PAH, MA-PAH exhibits a female predominance, which could be attributed to the estrogen paradox. Considering the ongoing rise in MA misuse in the United States and its potential implications for increased MA-PAH incidence in the near future, a comprehensive understanding of the pathophysiology of MA-PAH becomes imperative to identify preventive measures and develop effective treatments for this condition.

Funding/Support

Supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, United States [Grant R01HL152832 to N. K. D.].

Financial/Nonfinancial Disclosures

None declared.