US surveillance data indicate increases in drug overdose deaths involving methamphetamine.¹ Deaths involving psychostimulants other than cocaine (largely methamphetamine) increased 180% nationally, between 2015 and 2019.² The increase in methamphetamine use and related deaths and emergency hospitalizations has focused attention on the experience of methamphetamine “overdose”. Qualitative studies have determined that “overdose” may be an imprecise term for describing the experience of taking too much methamphetamine, which people who use drugs refer to as “overamping”.^3,4 In fact, when asked directly if they had ever experienced a “methamphetamine overdose,” respondents in a study in the Western US denied having had such an experience, though they did describe a host of other negative, unwanted, and medically concerning acute effects of consuming too much methamphetamine including physical (e.g., rapid heart rate, uncontrollable movements) and psychological symptoms (e.g., paranoia, anxiety, hallucinations)³ that ranged from expected drug effects to unexpected and worrisome. Given this diversity in the types and acuity of symptoms associated with taking too much methamphetamine,⁵ there are challenges in defining the experience of a non-fatal methamphetamine “overdose,” which has important implications for recognition in pre-hospital settings.

In contrast, identifying and measuring non-fatal opioid overdose is relatively straightforward, because the symptoms are less variable and more easily recognized (i.e., depressed respiration, loss of consciousness, and cyanosis).⁶ Therefore, training laypeople, in addition to emergency clinical personnel, to recognize and respond to opioid overdose has become commonplace. The first step of opioid overdose response - “recognition” - typically asks if a person has “became unconscious,” “stopped breathing,” or “had difficulty breathing” as a result of taking opioids.^7–9 If such symptoms are identified, the response steps (call 911, provide rescue breathing, administer rescue medication, provide follow-up care and support) follow logically from the primary symptom – depressed respiration. In contrast, identifying the experience of “overamping,” or symptoms of acute methamphetamine toxicity, is newer and more complex, thereby complicating recognition and response.

Harm reduction, pre-hospital, and clinical interventions designed to address non-fatal acute methamphetamine toxicity require that the phenomenon of interest is described accurately, and in all its complexity. To advance this goal, here we describe the prevalence and symptoms of acute methamphetamine toxicity, using a quantitative survey measure developed based on qualitative data³ about the symptoms of acute methamphetamine toxicity. Then, we compare the symptoms, demographic profiles, and substance use behavior/risk factors among people who experienced acute methamphetamine toxicity, opioid only overdose, and overdose including a mixture of opioids and methamphetamine. Implications for harm reduction, pre-hospital, and clinical interventions are discussed.

We used descriptive statistics to summarize the prevalence of each type of overdose or toxicity event (i.e., methamphetamine toxicity, opioid overdose, and mixed drug overdose). Then, we described the frequency of symptoms experienced at the most recent event, stratified by type of event. Finally, we compared demographics and drug use behavior across three groups: (1) those who only ever experienced opioid overdoses, (2) those who only ever experienced methamphetamine toxicity, and (3) those who only ever experienced drug mixture overdoses and those who experienced multiple types of overdoses/toxicity events. Because of small cell sizes in the drug mixture only group, and after comparing the participants in this group to those who experienced multiple types and determining that they are sufficiently similar, we collapsed these two categories to enable us to make statistical comparisons. We did not collapse race, despite small cell sizes, in the interest of documenting the racial diversity in the sample. This made a statistical comparison by race impossible. Because this analysis focused on the methamphetamine-only events, we used that as the reference point for comparisons. Statistical comparisons were made using Chi-square test or Fischer’s exact test for proportions, and Wilcoxon rank sum test for medians. All analyses were conducted in R.

This study provides important insights into the self-reported symptoms described by people who experienced acute methamphetamine toxicity, comparing these events with opioid overdoses and mixed drug overdoses. Our findings have implications for harm reduction, pre-hospital, and clinical interventions. Most importantly, while the demographic profiles of individuals experiencing different types of drug-related events are similar, the symptoms experienced during an episode of acute methamphetamine toxicity differ markedly from the symptoms experienced during an opioid overdose. Compared to opioid-involved events, which are characterized by depressed respiration and loss of consciousness, acute methamphetamine toxicity presents with distinct symptom clusters involving cardiovascular and psychiatric symptoms, clinically referred to as a sympathomimetic toxidrome.¹² Interestingly, mixed drug overdoses involving both opioids and stimulants primarily resembled opioid overdoses in their symptom profile, suggesting that the opioid component may dominate the clinical presentation in these cases. Therefore, care should be taken when describing acute non-fatal drug-related medical events to specifically define the type of event (i.e., opioid overdose vs. acute methamphetamine toxicity or “overamping”).

This diversity in symptom presentation for methamphetamine toxicity poses challenges for potential lay and emergency responders in recognizing and appropriately responding to these events. Qualitative data suggest that people who use drugs often deny the possibility of experiencing a methamphetamine “overdose” and some may lack a clear understanding of how to manage a potentially harmful methamphetamine-related event, making it difficult for them to identify when intervention is necessary.^3,4 Clinical evaluation and diagnosis is largely based on patient history and physical examination,¹² which relies on the clinician’s ability to ask the correct questions to obtain an accurate history and symptom profile. Asking about specific symptoms most frequently reported in acute methamphetamine toxicity events may inform more rapid and accurate diagnosis.

Our findings underscore the need for clear, evidence-based recommendations for responding to acute methamphetamine toxicity that can be easily understood and implemented by emergency responders and laypeople alike. Clinical recommendations for management of acute methamphetamine toxicity prioritize airway, breathing, and respiration; providing a calm safe environment; and offering medications such as benzodiazepines or antipsychotics to reduce toxicity symptoms including tachycardia, hypertension, agitation, seizures, and psychosis.^12,13 Practice-based experience in overdose prevention centers¹⁴ suggests additional recommendations for non-clinicians responding to suspected methamphetamine toxicity, including: 1: Recognizing signs of distress: anxiety, rapid heart rate, difficulty breathing, paranoia. 2: Providing a calm, safe environment to reduce stimulation and anxiety. 3: Encouraging the person to sit or lie down to prevent falls if dizziness occurs. 4: Offering cool water to prevent dehydration. 5: Monitoring breathing and consciousness. 6: Escalating to emergency services if symptoms worsen or persist, especially if the person experiences chest pain, symptoms of stroke, severe difficulty breathing, or loses consciousness. Messaging for laypeople should emphasize that while these steps can be helpful, professional medical evaluation may also be warranted in cases of suspected acute methamphetamine toxicity, given the potential for serious cardiopulmonary and cerebrovascular complications.

A concerning finding from our study is the significantly lower prevalence of naloxone availability among those who experienced methamphetamine toxicity only, compared to other groups. This disparity is worrying given the high prevalence of polydrug use and the potential for unexpected opioid exposure, even among primary methamphetamine users.¹⁵ The lower naloxone availability among people using methamphetamine may reflect a perception that they are not at risk for opioid overdose. However, given the unpredictability of the drug supply and the high prevalence of polydrug use, ensuring widespread naloxone access across all groups of people who use drugs remains crucial. Public health interventions should aim to increase naloxone distribution and education among people who use methamphetamine, emphasizing the importance of having this life-saving medication on hand regardless of one's primary drug of choice.

Several limitations should be considered when interpreting the results of this study. First, the cross-sectional nature of our design precludes the establishment of causal relationships and the convenience sampling and geographical focus of our study on four sites in Nevada and New Mexico may limit the generalizability of our findings to other regions with different drug use patterns. Second, while our sample size of 420 participants allowed for meaningful analyses, a larger sample might have provided greater statistical power, particularly for subgroup comparisons. Future research should aim to address these limitations through longitudinal designs, larger sample sizes, and more diverse geographical representation to further validate and expand upon our findings.

In terms of measurement limitations, our self-report measures were subjective, by design, and because they were derived from formative work describing participants’ experience of taking too much methamphetamine, some symptoms may not align with clinical diagnostic indicators. For example, the symptom “loss of consciousness (blacked out)” may represent two distinct clinical phenomena. But from the participant experience they are described similarly and therefore assessed using the same item. Similarly, some symptoms associated with methamphetamine use (but not necessarily acute toxicity) are not included, such as hyperactivity. The rationale for not including hyperactivity in the measure is that participants in our formative work did not identify that as an indicator of needing medical attention for an acute event. Finally, our measurement of acute methamphetamine toxicity did not account for unintentional exposure to opioids in methamphetamine (presumably through adulteration of methamphetamine). Given data from other studies indicating that the prevalence of unanticipated fentanyl in methamphetamine is <10%¹⁵ and that participants in this study had a remarkably low prevalence of unanticipated fentanyl exposure¹⁶ we do not believe this to be a major limitation of this study.

In conclusion, this study contributes valuable insights to the growing body of literature on a rising concern in public health: non-fatal acute methamphetamine toxicity. Our findings underscore the unique challenges in identifying and responding to acute methamphetamine toxicity in a pre-hospital environment and highlight the urgent need for targeted interventions. As methamphetamine use continues to increase across the United States and become more prevalent in areas that, heretofore, have had relatively low prevalence, it is crucial that we develop and implement comprehensive public education campaigns to raise awareness about the signs and symptoms of methamphetamine toxicity. These efforts should aim to empower people who use drugs, laypeople, and emergency responders with the knowledge and skills to recognize and respond appropriately to these events. Especially because people who use drugs experience significant barriers to accessing routine health care, acute emergency medical events can represent a unique moment for engagement, if thoughtful treatment and compassionate care are provided.

Our results emphasize the critical need for evidence-based interventions to prevent, reduce, and treat methamphetamine toxicity. This may include the development of novel harm reduction strategies specifically tailored to methamphetamine use, as well as the expansion of treatment options for methamphetamine use disorder. By addressing these needs, we can work towards mitigating the health impacts of methamphetamine use and improving outcomes for affected individuals and communities. Collaborative efforts among people who use drugs, researchers, harm reduction workers, healthcare providers, policymakers, and community organizations will be essential in translating these findings into effective public health strategies and clinical practices.