Since 2021, there has been a sharp increase in deaths attributed to acute toxicity from methamphetamine or cocaine (stimulants) in the United States.(1) Most of these deaths were also attributed to fentanyl, while deaths attributed to stimulants without opioid involvement have increased much less during that same period. For opioids, there is a clearly defined mechanism of overdose death, a process involving respiratory depression eventually resulting in cardiac arrest, and early evidence that deaths involving both opioids and stimulants have a similar etiology.(2, 3) However, the etiology of stimulant deaths that do not involve opioids is poorly understood.

Stimulant use is associated with a wide range of cardiovascular conditions. Coronary artery disease, congestive heart failure, electroconductive abnormalities, valvular disorders, aortic and coronary artery dissections, and both ischemic and hemorrhagic strokes can all result from long-term stimulant use, and raise the risk for future death from cardiovascular disease.(4-7) Studies in Australia identified cardiovascular disease, most commonly coronary artery disease, in 54% of methamphetamine deaths(8) and 51% of cocaine deaths(9); cerebrovascular disease was also more prevalent in stimulant compared to opioid deaths. An analysis of additional causes of death and significant contributing conditions among deaths attributed to acute toxicity from opioids or stimulants found similar odds of cardiovascular, cerebrovascular, and other medical contributors among opioid and opioid-stimulant deaths, and much higher odds among deaths attributed to stimulants alone.(10) Investigators have suggested that many deaths attributed to acute stimulant toxicity may actually be better attributed to chronic cardiovascular disease exacerbated by stimulant use.(11)

We analyzed data from a psychological autopsy study of deaths attributed to acute stimulant toxicity to understand the prevalence of pre-mortem cardiovascular disease in stimulant deaths by fentanyl involvement.

Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the corresponding author.

Decedent demographics are provided in Table 1. Median age was 58 years; 75% were male; 44% were White, 36% Black/African American, 14% Hispanic/Latine, and 4% Asian/Pacific Islander; 20% were unhoused and 49% were marginally housed. Stimulant-no-opioid deaths were significantly older (58 vs 50 years, p=0.02); other sociodemographic characteristics were similar by fentanyl involvement.

Overall, 86% of decedents had clinical evidence of pre-mortem cardiovascular disease and 68% had informant-reported pre-mortem potential cardiovascular symptoms (Table 2). Cardiovascular conditions were more common among stimulant-no-opioid decedents compared to fentanyl-stimulant decedents by record review (p<0.01) and informant report (p=0.02). The individual conditions that were significantly more prevalent among stimulant-no-opioid decedents were cardiac enlargement/ventricular hypertrophy (by autopsy, p=0.04), coronary artery disease (by autopsy, p=0.01), prolonged QTc interval (by electrocardiogram, p=0.03), and hypertension (by diagnostic code, p=0.02); shortness of breath in the year prior to death (by informant report) was marginal (p=0.05).

Our mixed-methods findings strongly support chronic cardiovascular disease, including cerebrovascular disease, as the primary etiology of deaths attributed to acute stimulant toxicity in the absence of opioids. While cardiovascular disease was prevalent among all deaths involving stimulants, findings on medical record review, as well as by informant report of symptoms, were greater among stimulant-no-opioid deaths than among fentanyl-stimulant deaths, further supporting the hypothesis that these categories of deaths are due to distinct processes.

We identified several specific cardiovascular signs and symptoms that were more prominent among stimulant deaths in the absence of opioids. Cardiac enlargement / left ventricular hypertrophy and coronary artery disease as found on autopsy, prolonged QTc interval as found on clinically-obtained electrocardiograms, and clinically-diagnosed hypertension were all highly prevalent and more frequently reported for stimulant-no-opioid deaths compared to fentanyl-stimulant deaths. These differences suggest potential targets for intervention, such as screening electrocardiograms for people who report stimulant use; more aggressive management of hypertension, coronary artery disease, and congestive heart failure; and a lower threshold for deploying strategies – such as statin therapies – to prevent or slow the progression of cardiovascular disease.(16) Shortness of breath was frequently reported and may represent a potential target for more aggressive diagnostic and therapeutic strategies.

Informants reported that cardiovascular disease (by family history and decedents’ symptoms at the time), poor mental health, recent declines in health, avoidance of non-urgent medical care, and social isolation were common among decedents at the time of death. Notably, all exemplar quotes were from informants for stimulant-no-opioid deaths. Informants generally felt that medical causes, such as heart attacks or strokes, were main contributors to the death of decedents rather than attributing their death to a single incident involving use of too much of a stimulant. While the symptoms themselves could have been related to an array of medical problems, not just cardiovascular disease, these findings overall support chronic disease as the major contributor to death, and reinforce the importance of interventions to engage people who use stimulants in primary care, cardiovascular specialty care, and substance use disorder treatment interventions.

The hypothesis that chronic disease is the underlying etiology of deaths attributed to acute toxicity from stimulants in the absence of opioids is now supported by multiple studies. From this same cohort, we found that deaths involving stimulants without opioids had less evidence of drug use on the scene of unwitnessed deaths and less drug use prior to events that led to death among witnessed deaths, when compared with fentanyl-stimulant deaths.(3) While stimulants can be directly responsible for acute myocardial infarctions, arrythmias, or cerebrovascular accidents, the occurrence of these events is strongly associated with both aging and cumulative exposure to the substance(17); this extends to prescribed psychostimulants, for which duration of use is also associated with cardiovascular outcomes.(18)

The substantial prevalence of cardiovascular disease in fentanyl-stimulant deaths supports similar intervention efforts for this population as well. Nonetheless, other analyses of this dataset suggest that the mechanism of acute death in fentanyl-stimulant cases was more likely opioid-induced respiratory depression,(3) thus opioid-based overdose prevention interventions like naloxone provision are also critical for people who use stimulants. People who use stimulants may use fentanyl intentionally, and thus should be aware of opioid overdose risks. However, about a third of paramedic-managed opioid overdoses in San Francisco were among people who used stimulants and did not intend to use any opioid – these events were attributed to unintentional fentanyl use.(19) Interviews suggest that these patients had used drugs that they thought were stimulants, but were in fact fentanyl, or had used drug paraphernalia that they did not know had been used for fentanyl administration.(19) Broad opioid overdose education and naloxone provision for people who access any non-prescribed drugs is critical to reduce fentanyl-involved deaths, and strategies to slow or reverse cardiovascular disease are critical for people who use stimulants regardless of other substances used.

The question of how stimulants contribute to opioid overdose deaths remains poorly understood. While stimulants may merely be a bystander, some have suggested that, by increasing myocardial demand, stimulants increase susceptibility to opioid-induced respiratory depression. This hypothesis is belied by decades of anesthesiology and other research suggesting that stimulants often raise the threshold for respiratory depression from opioids.(20-22) A corollary hypothesis suggests that, by increasing cardiovascular disease, chronic stimulant use creates a physiologic milieu more susceptible to cardiac arrest when respiratory depression occurs from opioid use; i.e., rather than acutely contributing to an opioid death, stimulants contribute through the pathway of chronic disease. A different set of hypotheses suggests that the higher risk of opioid overdose death among persons who also use stimulants is due to behavioral factors. Stimulant use is associated with high risk sexual behaviors,(23-25) which may extend to opioid use practices that increase overdose risk. Alternatively, by raising the threshold for respiratory depression from opioids,(20-22) stimulant use may allow people to use higher doses of opioids (supported by studies demonstrating a median dose of fentanyl of >1.5 grams with near-universal stimulant use(26)); this apparent protection, however, would be dependent on the presence and dose of stimulants. Thus the risk of opioid overdose may increase not only due to shifts in the potency of the available opioid,(27) but simultaneous shifts in the presence and potency of stimulants, making street opioid use increasingly perilous to titrate.

The primary limitations of this study were the small sample size and single geographic location, both of which limit generalizability. A larger sample size or more geographic diversity may have identified more varied medical backgrounds among decedents. In addition, only decedents for whom an informant could be found to interview were included in the study, which could underestimate the degree of social isolation in the overall population. Informant accounts may also be subject to recall bias or influenced by social desirability, leading to a desire to attribute a loved one’s death to less stigmatized medical causes. Finally, while the high prevalence of pre-mortem cardiovascular disease was likely contributed to by stimulant use, it may have also involved other factors; low income, racial/ethnic minority status,(28) and housing challenges(29) have all been associated with accelerated cardiovascular disease. While efforts to address substance use are critical, more comprehensive efforts addressing broader social determinants of health may be necessary to reduce adverse cardiovascular outcomes.

In summary, we found a high prevalence of pre-existing cardiovascular disease and potential cardiovascular symptoms among deaths attributed to acute stimulant toxicity, with an even greater prevalence among those deaths attributed to stimulants in the absence of opioids. These findings support the hypothesis that stimulant deaths in the absence of opioids are distinct from those involving fentanyl. Moreover, findings suggest that preventing these deaths would require aggressively screening for, preventing, and treating chronic cardiovascular conditions.