Marked Improvement in Pulmonary Arterial Hypertension in 3 Patients with a History of Amphetamine-like Drug use and Comorbidities

1. INTRODUCTION

Amphetamine-like drugs and amphetamine abuse have been associated with Pulmonary Arterial Hypertension (PAH) [1, 2]. Fenfluramine and dexfenfluramine are methamphetamine-like drugs that have been linked to the development of PAH [3]. Patients with amphetamine-associated PAH are generally lumped together with the entire cohort of PAH patients in large studies; therefore, their prognosis has been incompletely defined. Three patients with PAH, a history of amphetamine-like drug use and comorbidities, and catheterization-proven near-normalization of pulmonary arterial pressures are described.

A literature review was performed using the search engines PubMed, Google Scholar, ScienceDirect, publisher archives (e.g., Elsevier, SpringerLink), and ChatGPT. The following terms were used in the search: pulmonary hypertension and amphetamines, methamphetamines, amphetamine-like drugs, appetite suppressants, anorexigens, drug-induced, diet pills, and follow-up catheterization data. Candidate citations were identified by ChatGPT and were later verified in PubMed. No early date limit was set on the search. The search period extended through October 2025. Decisions regarding which articles to include in the paper and the table were made by author AR. Comparative cohorts reporting survival or clinical worsening in drug-associated PAH were included.

Over 40 articles were reviewed, of which 17 studies were included in the summary. Of these, 6 included catheterization-confirmed hemodynamic data from follow-up. Articles with more than 3 patients and/or good hemodynamic data were included.

Informed consent for the publication of patient information was obtained from the patients. There are molecular structural similarities for amphetamines, methamphetamines, fenfluramine, and dexfenfluramine; therefore, in this manuscript, they are referred to as “amphetamine-like” drugs.

2. CASE REPORTS

3. LITERATURE REVIEW

Table 2 summarizes reports that describe worse, similar, or better prognoses in patients with PAH associated with methamphetamine-like drugs compared with patients who have PAH of different etiologies (mostly idiopathic).

Among those reporting worse survival for patients with amphetamine-associated PAH, Rich et al. [4] compared 10 patients with fenfluramine-associated PAH and 70 patients with primary PAH, all treated with epoprostenol. Median survival was 14 months in the fenfluramine group, compared with 49 months in the primary PAH group. Zamanian et al. [5] studied 90 patients with methamphetamine-associated PAH and 97 patients with idiopathic PAH. Patients with methamphetamine-associated PAH had a higher incidence of heart failure symptoms, higher right atrial pressure, lower stroke volume, and more than double the risk of clinical worsening or death.

Others have described similar survival for patients with fenfluramine-associated PAH vs idiopathic PAH. Souza et al. [6] studied 109 patients with fenfluramine-associated PAH, some of whom also used amphetamines. The acute response to vasodilator testing was 8.3%, BMPR2 mutations were present in 22%, and the median survival was 6.4 years, similar to that of patients with idiopathic PAH. Brenot et al. [1] reported on 73 patients with PAH treated with epoprostenol; 15 (20%) had a history of fenfluramine use, 10 of whom had a positive vasodilatory response. Survival was similar in the fenfluramine vs non-fenfluramine groups. Three of the 15 fenfluramine PAH patients showed short-term clinical or hemodynamic improvement. One had a drop in pulmonary vascular resistance from 35 to 15 Wood units at 12 months. The second patient had a drop in pulmonary vascular resistance from 24 to 10 Wood units at 6 months but died 2 years later. The third patient had a decrease in pulmonary vascular resistance from 19 to 10 Wood units at 3 months, but had evidence of moderate pulmonary hypertension 4 years later. Simmoneau et al. [7] reported on 62 patients treated with fenfluramine derivatives (17 also used amphetamines) and 125 control patients with primary PAH. Survival was similar for both groups, 50% at 3 years. Uhland et al. [8] treated 64 patients with methamphetamine-associated PAH and 74 patients with IPAH with subcutaneous treprostinil. Transplant-free survival was similar: 84% at a mean follow-up of 46 months for the methamphetamine PAH group and 72.9% at a mean follow-up of 67 months for the IPAH group. Kolaitis et al. [9] reported data from the US-based Pulmonary Hypertension Association Registry, comparing 118 patients with methamphetamine-associated PAH and 423 patients with IPAH. Survival was similar in the 2 groups. O’Neill et al. [10] reported on 51 patients with methamphetamine-associated PAH versus 51 patients with IPAH; survival was similar at 5 years. Mlczoch et al. [11] described no difference in survival in 75 patients with and without anorectic drug use; none of the patients had normalization of pulmonary arterial pressure. Haddad et al. [12] found no difference in survival between 44 patients with IPAH and 51 patients with drug- or toxin-induced PAH.

A limited number of publications describe a better prognosis or improvement in catheterization-confirmed hemodynamics in patients with PAH associated with anorexigen drug use compared to PAH of other causes. Loogen et al. [13] reported on 24 patients with primary PAH and 18 patients with PAH and a history of anorexigen drug use. The 10-year survival rates were 0.31 versus 0.63, respectively. The mean pulmonary artery pressure increased in the primary PAH group from 48.8 to 61.0 mmHg, while it decreased in the anorexigen PAH group from 47.6 to 33.3 mmHg. Douglas et al. [14] described 2 patients with PAH related to previous fenfluramine use. One patient showed a decrease in mean pulmonary artery pressure from 32 to 11 mmHg over one year. The second patient experienced a decrease from 37 to 30 mmHg after 34 weeks. Pouwels et al. [15] reported one patient who previously used fenfluramine for 11 months. Over a three-month period, the mean pulmonary arterial pressure decreased from 47 to 16 mmHg.

4. DISCUSSION

Drug-induced pulmonary hypertension is rare, accounting for 10% of cases with PAH [16]. Aminorex, fenfluramine, dexfenfluramine, phentermine, and amphetamine-like drugs have been associated with the development of pulmonary arterial hypertension [1-3, 5, 16]. There are molecular structural similarities between amphetamines, methamphetamines, fenfluramine, and dexfenfluramine [17]. Several patients who take anorexigens also use methamphetamines [6, 7]. Therefore, the literature on pulmonary hypertension associated with both amphetamines and anorexigens (collectively referred to as “amphetamine-like”) was reviewed. Few publications have reviewed the prognosis of patients who have PAH associated with amphetamine-like substances, often with contradictory results and a scarcity of follow-up hemodynamic data. In comparison to idiopathic or other secondary PAH, the prognosis of patients with amphetamine-like drug use/abuse has been reported to be worse [4, 5], the same [1, 6-12], or better [13-15].

Catheterization data on three patients with pulmonary hypertension and a history of anorexigens or amphetamine-like drug use are described. Two of the 3 patients had sleep apnea and long-term CPAP therapy. The same 2 patients were responders to vasodilator testing. Long-term therapy in the 3 patients included: nifedipine, sildenafil, ambrisentan, and selexipag in patient 1, bosentan in patient 2, and sildenafil and macitentan in patient 3. All 3 patients were overweight. One of the patients experienced significant weight loss following bariatric surgery. At that time, her hemodynamics had already shown substantial improvement. At the most recent catheterization in the 3 patients, the mean pulmonary arterial pressure was 20, 23, and 21 mmHg, and the unindexed pulmonary vascular resistance was 0.9, 1.7, and 1.9 Wood units, respectively. Therefore, using contemporary PAH thresholds [18], the patients had borderline elevated pulmonary arterial pressure but normal pulmonary vascular resistance.

This manuscript’s main strength lies in the longitudinal invasive hemodynamic follow-up spanning many years, including serial right heart catheterizations and vasoreactivity testing in two patients, culminating in mean pulmonary artery pressures in a near-normal range. Such extended catheter-based follow-up is uncommon in published case literature. A second strength is the attempt to synthesize discrepant prognostic findings across studies that have reported worse, similar, or better outcomes in drug-associated PAH compared with idiopathic PAH, and to highlight the scarcity of repeated hemodynamic measurements in many cohorts.

This case series has several limitations. Two of the 3 patients had sleep apnea and were treated with long-term CPAP. It is possible that the CPAP contributed significantly to their improved hemodynamics. However, most reports of pulmonary hypertension associated with sleep apnea show only mild elevation of pulmonary arterial pressures as well as modest improvements in pressures with CPAP therapy [19]. Only three patients who demonstrated catheterization-proven hemodynamic improvement are described, and the total number of patients with similar etiology of PAH from which these cases were selected is not available. It is estimated that approximately two to three additional patients with amphetamine-associated PAH were evaluated and treated at the institution during the same timeframe. One of these patients showed echocardiographic normalization of pulmonary arterial pressure, as indicated by tricuspid regurgitation jet velocity, but was not included in this series due to refusal of catheterization secondary to lack of insurance coverage. The remaining patients have not undergone serial catheterizations. Therefore, the clinical trajectories of the 3 cases presented in this paper may still not be typical or clearly representative of methamphetamine-associated PAH. Additionally, 2 of the 3 patients were vasoreactive, in which case a hemodynamic improvement with therapy would be expected. However, whether this is solely related to the drug-associated PAH or these patients may have a different etiology for the PAH (such as sleep apnea) and were in a favorable prognostic group, cannot be discerned. Only one of the 3 patients underwent genetic testing (patient 3 was positive for a BMPR2 mutation), and the effects of the genetic substrate in this patient and others remain to be determined. Evans et al. showed a worse prognosis in patients with BMPR2 mutations compared with patients with idiopathic PAH [20]. (Jonathan Evans, Lancet 2016). In Table 2, the studies were pooled; however, they represent different eras, treatment modalities, and endpoints and may not be directly comparable. While the use of fenfluramine has decreased in the population (now used mainly for seizure control and at lower doses), the illicit and licit use of methamphetamine and amphetamine has increased significantly in the last 2 decades.

CONCLUSION

In summary, there are limited and somewhat contradictory data on the long-term prognosis of patients with amphetamine-associated pulmonary hypertension. Most publications suggest that the survival of amphetamine-like drug-associated PAH is similar to that of idiopathic PAH. Hemodynamic data documenting the progress of patients are, however, scarce. Three patients with PAH, a history of amphetamine-like drug use and comorbidities (sleep apnea in two and a genetic mutation in one), and catheterization-proven near-normalization of pulmonary arterial pressure are described. The hemodynamic improvement may represent a treatment-associated course, the treatment of additional comorbidities in 2 of them, or possibly an intrinsically better natural history in selected patients. Hemodynamic data from more patients are necessary to make more definitive statements about physiologic evolution, the optimal choice of specific pulmonary hypertension medications, and prognosis in cases of the different amphetamine or amphetamine-like drug-associated forms of PAH.

REFERENCES