Methamphetamine and the risk of pulmonary arterial hypertension

Abstract

Purpose of review

Methamphetamine is a highly addictive drug originally developed for the treatment of neuropsychiatric disorders. At present, the epidemic rise of illicit methamphetamine use has increased the number of patients living with medical complications. Our group has recently identified a definite association between methamphetamine use and pulmonary arterial hypertension (PAH), a life-threatening disease characterized by occlusive vasculopathy and progressive right heart failure. This review will discuss the evidence that links methamphetamine with PAH and how to approach the diagnosis and management of methamphetamine-associated pulmonary arterial hypertension (Meth-APAH) patients in clinic.

Recent findings

Compared with idiopathic (I) PAH, Meth-APAH patients present with worse functional status, right ventricular dysfunction, and exercise tolerance. Despite therapy, the 5-year survival of Meth-APAH patients is significantly lower compared with IPAH. Genetic studies suggest that loss of function variants in genes involved in drug detoxification can increase susceptibility for methamphetamine-related vascular injury and trigger occlusive vasculopathy.

Summary

PAH patients undergoing diagnostic evaluation should be screened for a history of current or past methamphetamine use. Pharmacovigilance should be implemented to monitor patients being treated with methamphetamine for neuropsychiatric disorders (e.g., attention-deficit hyperactivity disorder). More studies will be needed to identify which susceptibility factors increase risk of PAH in methamphetamine users.

INTRODUCTION

Pulmonary arterial hypertension (PAH) is a life-threatening disease which causes progressive dyspnea, right ventricular failure, and eventual death. It is characterized by severe small vessel loss, obstructive vasculopathy, and a mean pulmonary artery pressure greater than 25 mmHg. Historically, PAH was first described in 1891 by the German physician Romberg [1]. However, in the decades following its discovery, PAH would be widely regarded as a rare disease with few cases being reported on a yearly basis. It would not be until the late 1960s that PAH would garner global attention from the medical community as a surge of new cases were being reported in association with anorexigen drug (amphetamine-like appetite suppressant) use in Germany, Austria, and Switzerland [2]. Given these historical events and the increase in reported cases of PAH, an international meeting was held in 1973 by the WHO to discuss the current state of knowledge regarding the disease, establish nomenclature, and create the classification scheme that remains in use to this day [3].

To date, several drugs and toxins have been identified and implicated as risk factors for PAH. The different drugs and toxins are classified as “definite,” “likely,” and “possible” risk factors [4]. Drugs and toxins considered “definite” risk factors for PAH include anorexigens such as Aminorex Fumarate, Fenfluramine (used alone or combined with phentermine in a compound commonly referred to as “fen-phen” in the United States), and Benfluorex (another amphetamine-like appetite suppressant drug that was marketed as an antidiabetic agent in France until 2009, but used between 1998 and 2009 as a replacement for the withdrawn fenfluramine derivatives). New data have also allowed us to identify chemotherapeutic agents, such as the tyrosine kinase inhibitor, Dasatinib [5] as “likely” risk factors for PAH. Other agents in the “possible” category include interferon (used in the treatment of diseases such as viral hepatitis and multiple sclerosis) [6] cocaine [7], as well as the widely available herbal supplement, St. John’s Wort.

Among these drugs and toxins, (meth)amphetamines are considered “likely” risk factors for PAH. Recent studies and data are beginning to further elucidate the connection between amphetamine derivatives and their associated risk of PAH. Novel clinical trials and mounting basic science research are beginning to shed light on this increasingly apparent connection. Although there are many drug and toxins which are currently implicated as risk factors for PAH, this review will focus specifically on methamphetamine. We refer readers to several review articles in the literature which cover the current state of knowledge regarding other drugs and toxins and their association with PAH [8,9].

INTRODUCTION TO METHAMPHETAMINE

Methamphetamine is a highly addictive derivative of amphetamine that was originally developed as a medical therapy for attention-deficit hyperactivity disorder, narcolepsy, and obesity. Methamphetamine can be inhaled (vaporized), smoked, snorted, orally ingested, or injected intravenously. Methamphetamine produces central nervous system (CNS) stimulation by promoting the release of the neurotransmitters serotonin, dopamine, and norepinephrine [10]. This produces some of the desired effects which include euphoria, increased energy, focus, and decreased appetite. However, many well-known deleterious effects of methamphetamine have also been identified including CNS toxicity [11] and cardiomyopathy [12].

EPIDEMIOLOGY AND BURDEN OF DISEASE

Methamphetamine use has continued to rise in recent years. A 2018 New York Times article heralds the return of methamphetamine as a major public health concern and highlights its increasing use and popularity in the United States [13]. The 2017 United Nations Office on Drugs and Crime report states that, after opioids, amphetamines are the second most abused drug in the world and methamphetamine represents the greatest global health threat [14]. NIH data from 2013 shows that 1.2 million people or roughly 0.4% of the US population reported methamphetamine use in the past year [15]. Data from The Monitoring the Future Study in 2017 showed that 1.10% of all 12th graders in the United States had used methamphetamine in the past year [16]. A national survey on drug use and health in the United States estimated that in 2016, 684 000 people aged 12 years and over had a methamphetamine use disorder [17].

The healthcare cost associated with methamphetamine is also significant, with recent reports estimating total costs of methamphetamine near 23.4 billion dollars when one factors hospital costs, lost productivity, premature death, and even burns from its highly explosive manufacturing process [18]. According to a report by the Drug Abuse Warning Network, methamphetamine accounted for about 103 000 emergency department visits in 2011 [15].

THE CALIFORNIA METHAMPHETAMINE EPIDEMIC

In the United States, western states, particularly California, are regarded as “hot spots” for methamphetamine activity. According to a National Institute of Drug Abuse Community Epidemiology Work Group report, methamphetamine’s effects are most felt in Western and Midwestern regions of North America. In the first half of 2012, methamphetamine ranked first in drug-related treatment admissions in Hawaii and San Diego, second in San Francisco, and third in Denver and Phoenix [15]. Research from Gruenewald et al. [19] has shown that methamphetamine usage exhibited growth and spatial spread characteristic of that of other drug epidemics. From 1983 to 2008 the incidence of methamphetamine abuse and dependence presenting to hospitals in California increased 13-fold; between 1999 and 2008, methamphetamine usage increased exponentially at a rate of 17% per year [19].

OPIATES AND THE METHAMPHETAMINE EPIDEMIC

In recent years much attention has been given to the prescription opioid epidemic in the United States. It is currently regarded as one of the most important public health concerns in the country and has garnered strong federal and political support in efforts to curb its spread and growth [20]. Although not as publically featured in the media, there are data supporting that methamphetamine use and its associated comorbidities may present an almost equally challenging and important public health concern, especially in the western United States. A recent article reports that although the concern over the opioid epidemic is justified, it has overshadowed a worsening methamphetamine drug problem [21]. Recent data from a study in San Francisco showed that between 2005 and 2015 individuals who died from drug-related cardiac conditions or cerebral hemorrhage had higher odds of death because of acute toxicity from stimulants compared to opioids [22]. Increasing use of methamphetamine is also becoming recognized as a major public health concern in Australia and Southeast Asia, where some reports state it may be the most commonly abused drug in those regions, even more so than opiates [23].

METHAMPHETAMINE-RELATED MEDICAL COMORBIDITIES

There are many well-recognized medical comorbidities associated with methamphetamine use. These include ischemic cardiomyopathy, arrhythmias, hypertension, cerebrovascular accidents, CNS toxicity, psychosis [24] a withdrawal/abstinence syndrome [25], and renal and liver failure [26]. Given recent trends in the popularity of methamphetamine use, we speculate that we are going to continue to see more methamphetamine-related medical comorbidities in the coming future.

METHAMPHETAMINE AND PULMONARY ARTERIAL HYPERTENSION

Initial suspicion regarding an association between methamphetamine and PAH was first reported in 1993 by Schaiberger et al. [27] who published the case of a truck driver who was a long-term user of “crank” methamphetamine (crank is a commonly used nickname for methamphetamine) and subsequently went on to develop severe PAH. After an exhaustive diagnostic workup, alternative causes failed to be identified and the authors concluded that the development of PAH was most likely secondary to methamphetamine use. This association was reasonable given the fact that methamphetamine and Aminorex Fumarate, a known risk factor for PAH, share a similar chemical structure [27].

In 2006, Chin et al. [28] conducted one of the first clinical retrospective cohort studies looking at methamphetamine and the risk of PAH. They looked at rates of stimulant use in 340 patients and defined stimulant use as cocaine, amphetamine, or methamphetamine. They were able to show that a history of stimulant use was found in 28.9% of patients with a diagnosis of ‘idiopathic PAH’ (IPAH) compared with only 3.8% of patients with a diagnosis of PAH and known risk factors, and only 4.3% of patients with chronic thromboembolic pulmonary hypertension (PH). Patients with IPAH were approximately 10 times more likely to have a history of stimulant use than patients with PAH and known risk factors, and almost eight times more likely to have a history of stimulant use than patients with chronic thromboembolic PH, after adjustment for age. Not surprisingly, these ratios were similar to those found in studies of Fenfluramine use (a known risk factor for PAH) [28].

In the first prospective cohort study looking at patients with methamphetamine-associated pulmonary arterial hypertension (Meth-APAH), we recently published our findings comparing the clinical presentation, disease characteristics, and outcomes of patients with Meth-APAH to those with IPAH. We prospectively followed 187 patients who presented to the Stanford Adult PH program between 2003 and 2015 with either a diagnosis of Meth-APAH or IPAH. These patients underwent echocardiography, pulmonary function testing, chest imaging, and right heart catheterization. The primary outcome of the study was all-cause mortality, transplantation, or hospitalization for right heart failure. We also analyzed statewide California hospitalization data to determine outcomes of patients with International Classification of Diseases (ICD) coding indicative of Methamphetamine use and concomitant PAH. We found that Meth-APAH was more common in men and patients were more likely to inhale the drug through smoking. Pathologic lung samples were taken from both cohorts of patients, either at time of transplantation or autopsy, which showed characteristic vascular changes similar to those of IPAH, including angiomatoid plexiform lesions with slit-like vascular channels within the arterial lumen, as well as venoocclusive disease (Fig. 1). Despite similar pathologic changes, Meth-APAH presents with a more severe phenotype of clinical disease. Kaplan–Meier analysis showed a 5-year and 10-year event-free survival of 47.2 and 25%, respectively in Meth-APAH vs. 64.5 and 45.7% in IPAH (Fig. 2). Meth-APAH patients had higher right atrial pressures, lower stroke volume index, and more dilated, dysfunctional right ventricles when compared to patients with IPAH. Meth-APAH was also associated with an increased risk of heart failure, transplantation, and death, even when accounting for confounding variables such as socioeconomic status and age.

FIGURE 1.

Histopathology of Meth-APAH and IPAH. Panel A: normal muscular pulmonary artery. Panel B: plexiform lesion in patient with IPAH who underwent lung transplantation. Panel C: plexiform arteriopathy in Meth-APAH involving muscular artery. Panel D: high-power magnification showing proliferation of slit-like vascular channels within artery. Panel E: pulmonary microvasculopathy in Meth-APAH. Panel F: high-power magnification showing proliferation of capillaries within the pulmonary interstitium. Panel G: angiomatoid lesion in Meth-APAH composed of dilated, thin-walled vascular spaces surrounding a plexiform lesion. Panel H: the patient in panel G also exhibited scattered intravascular collections of microcrystalline cellulose (a filler commonly used to “cut” amphetamines), causing an intimal proliferative response within the muscular artery. IPAH, idiopathic pulmonary arterial hypertension; Meth-APAH, methamphetamine-associated pulmonary arterial hypertension. Reproduced with permission [29^■■].

FIGURE 2.

Kaplan–Meier plot comparing event-free survival in Meth-APAH patients vs. iPAH patients. Kaplan–;Meier estimated event-free survival demonstrates worse outcomes for patients presenting with Meth-APAH (dashed line) as compared to those with iPAH (solid line). iPAH, idiopathic pulmonary arterial hypertension; Meth-APAH, methamphetamine associated pulmonary arterial hypertension. Reproduced with permission [29^■■].

Interestingly, despite the fact that Meth-APAH patients were less likely to be treated with intravenous (IV)/subcutaneous prostacyclin analogs compared with IPAH patients, these factors did not explain the worse outcomes observed in a multivariable analysis. There was a reluctance by the clinical teams to use IV prostacyclin analogs in Meth-APAH patients given concerns regarding appropriate central line/skin site care and safety (i.e., risk for misusing venous lines). Furthermore, using a comprehensive large state-wide hospital database, we were able to show that hospitalized methamphetamine users appear to have a 2.6-fold increase risk of having an ICD-coded diagnosis of PAH compared with nonusers. We concluded that Meth-APAH has a worse prognosis than IPAH which is not attributable to worse baseline ventricular function, lower socioeconomic status, or lack of adherence [29^■■].

DISEASE/PROPOSED MECHANISMS

Although the true underlying mechanisms of Meth-APAH are currently unknown, several theories have been proposed. Elegant nuclear medicine studies with the use of radiolabeled methamphetamine analogues and PET scans have demonstrated that methamphetamine concentrations accumulate highest within lung tissue, which could possibly lead to greater pulmonary toxicity and vascular damage (Fig. 3) [30]. Concerning molecular mechanisms, serotonin has been proposed as a major driver of cell-driven vascular remodeling. For instance, serotonin stimulation can promote pulmonary smooth muscle cell proliferation, which leads to arterial luminal narrowing and increased pressures; in addition, methamphetamine can also damage pulmonary endothelial cells through the generation of toxic reactive oxygen species and mitochondrial dysfunction [31^■,32^■].

FIGURE 3.

Whole body images of radiolabeled methamphetamine in an African-American and in a White. Note the higher accumulation of radiolabeled methamphetamine in the lungs of the African-American. The hot spot on the abdomen of the White study participant represents the stomach, where radiolabeled methamphetamine accumulation was high but variable across study participants (may reflect the acidic environment of the stomach that favors trapping methamphetamine, which is a weak base). Reproduced with permission [30].

Many of the neuropsychiatric effects methamphetamine exerts are linked to direct alterations in serotonin [5-hydroxytryptamine AKA serotonin (5HT)] signaling activity. Serotonin is a neurotransmitter known for its involvement in the regulation of mood and appetite, but it is also produced by platelets to induce vasoconstriction at sites of vascular injury [33]. The biological effects of serotonin are mediated in two ways: through interaction with surface receptors (5HT_1A and 5HT_1B) and internalization via the serotonin transporter [serotonin transporter or 5HT transporter (5HTT)]. In the lung, serotonin has been shown to promote vascular remodeling and development of PAH by acting on 5HT_1B and 5HTT in pulmonary smooth muscle cells [34]. This is relevant to Meth-APAH as methamphetamine administration to monocrotaline-treated rats can cause severe vascular remodeling that is associated with a significant increase in expression of 5HT_1B and 5HTT within the pulmonary arteries [35]. It is worth mentioning that use of the serotonin inhibitor, fluoxetine, was capable of ameliorating the severity of vascular remodeling in methamphetamine-treated monocrotaline rats, raising the possibility that pharmacological inhibition of serotonin signaling could be a possible treatment for Meth-APAH. However, it is important to point out that recent studies using rats with a loss of function mutation in 5HTT were not protected from PAH, indicating that serotonin signaling is not the only major player in triggering pulmonary vascular remodeling [36]. At this time, we do not endorse the use of selective serotonin reuptake inhibitors or other types of serotonin inhibitors for treatment of Meth-APAH or any other form of PAH.

One major feature of Meth-APAH is that only a subset of methamphetamine users develop PAH, which likely denotes that there is a genetic component involved in pathogenesis. Some authors have theorized that perhaps there is a “two-hit phenomenon” in the development of PAH, with the first hit being a genetic mutation which renders an individual susceptible to developing PAH and then a second environmental trigger, such as methamphetamine exposure, is required to produce phenotypic disease [37]. Recent studies have used whole exome sequencing to identify a gene that may play a role in Meth-APAH pathogenesis. Carboxylesterase 1 (CES1) is a gene involved in drug metabolism that codes for an enzyme required for the detoxification of a variety of drugs, including cocaine, heroin, and methylphenidate (AKA Ritalin). Studies in explanted lung tissue have shown that this enzyme is predominantly expressed in pulmonary microvascular endothelial cells from healthy but not Meth-APAH patients (Fig. 4). Reduction of CES1 in healthy pulmonary microvascular endothelial cells increase methamphetamine-induced apoptosis through the deleterious generation of reactive oxygen species and alterations in autophagy, a stress-related response initiated by cells to allow repair [32^■]. Whether pharmacological agents that restore CES1 would serve as therapeutic agents in Meth-APAH patients remains to be determined.

FIGURE 4.

CES1 expression is reduced in vascular lesions of METH-PAH. Representative immunofluorescence studies of lung sections stained for CES1 (red) obtained from a healthy donor (top) and four METH-PAH patients. CD31 (green) stains for endothelial cells. CES1, carboxylesterase 1; METH-PAH, methamphetamine-associated pulmonary arterial hypertension. Reproduced with permission [32^■].

CLINICAL RELEVANCE AND FUTURE DIRECTIONS

Currently, methamphetamine is considered a “likely” risk factor for PAH by the WHO. Given the increasing data and evidence supporting a strong connection between methamphetamine and PAH, it may soon be changed to a “definite” risk factor [38], as discussed at the 2018 World Symposium on PH in Nice, France. It is important for clinicians to be aware of this connection and to engage in preventive efforts to improve patient outcomes. An important area of research at this time centers around using genomic data and gene screening to determine if we can identify methamphetamine users at risk for developing PAH at early stages. We are continuing to seek out candidate genes implicated in the pathogenesis of this disease. Clinicians should take an active role with their at-risk patient populations and take a thorough drug use history to uncover any evidence of prior or current methamphetamine use. In addition, any patient with a diagnosis of PAH should be screened, using blood or urine toxicology tests, to identify patients suspect of being active methamphetamine users. It may also be useful to employ random spot toxicology screening for former methamphetamine users as recurrence is high [39].

The therapeutic approach to Meth-APAH is similar to the standard care provided to patients with other forms of PAH. However, data from our prospective study demonstrated that in general, less Meth-APAH patients had robust responses to inhaled nitric oxide challenge, which predicts a diminished response to certain therapeutic agents (i.e., calcium channel blockers) and lower long-term survival [40]. Given our findings in our recent published work [29^■■], therapy selection is a major challenge in Meth-APAH patients. It also underscores the fact that ultimately, prevention may be our best form of therapy for these patients.

Methamphetamine was originally developed for the medical treatment of various neuropsychiatric disorders (i.e., attention-deficit hyperactivity disorder and obesity) and continues to be used for these conditions in modern practice. It is important to routinely screen patients on therapeutic methamphetamine for early signs of PAH. In addition, as the current iatrogenic opioid epidemic has shown us, we must be cautious when prescribing methamphetamine for medical conditions to avoid causing another life-threatening iatrogenic drug epidemic.

CONCLUSION

In conclusion, methamphetamine is a highly addictive drug that is being increasingly abused worldwide. Methamphetamine is now cheaper, purer, and more widespread than ever before. It is responsible for a large burden of morbidity and healthcare costs. There are well-recognized cardiac and CNS complications of methamphetamine use and PAH should now be added to this list. New studies have demonstrated a definite association between methamphetamine use and a more severe, progressive form of PAH with poor outcomes. These patients are more refractory to standard therapies and have a worse prognosis when compared with IPAH patients. Active research efforts are ongoing to understand the molecular mechanisms and genetic underpinnings responsible for the pathogenesis of this disease. Thus far, a few promising candidate genes involved in drug detoxification and protection from oxidative stress have been identified. Future studies using precision medicine tools such as gene sequencing and bioinformatics are needed to identify which susceptibility factors increase the risk of PAH in methamphetamine users.

There is much attention in the media and medical literature dedicated to the current prescription opioid epidemic; however, we must remain cognizant of the importance of methamphetamine abuse and its devastating medical consequences. We must also make a concerted effort to increase pharmacovigilance by practicing physicians and promote close interactions between drug regulatory agencies, national PH networks, and PAH patient associations as prevention may be our best strategy to combat this life-threatening drug-induced form of PAH.

KEY POINTS.

• Methamphetamine is currently classified as a “likely” risk factor for PAH; however, results of new studies may upgrade it to a “definite” risk factor.

• Despite therapy, Meth-APAH patients present with a more severe clinical course and have poorer long-term outcomes and prognosis, when compared with IPAH patients.

• The exact mechanism behind Meth-APAH is unclear, however, it may involve genetic mutations in genes that code for enzymes involved in drug detoxification.

• Clinicians and the public must remain aware and practice pharmacovigilance to identify these patients early and prevent further spread of the disease.

• Although the opioid epidemic is commonly featured in the media and medical literature, it is important to remain cognizant of the growing methamphetamine problem and its associated medical complications.