IT IS NO LONGER JUST AN OPIOID PROBLEM: POLYSUBSTANCE MISUSE AND THE FOURTH WAVE OF THE OVERDOSE CRISIS
Faculty:
L. Austin Fredrickson, MD, FACP
L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care.
Gerald Gianutsos, PhD, JD
Dr. Gianutsos is an Emeritus Associate Professor of Pharmacology at the University of Connecticut School of Pharmacy. He graduated with a B.S. in Pharmacy and M.S. in Pharmacology from St. John’s University. He received a Ph.D. in Pharmacology from the University of Rhode Island and a J.D. degree from the University of Connecticut School of Law. He completed a post-doctoral research fellowship at the Michigan State University School of Medicine. He was a member of the pharmacy faculty at UCONN for almost 40 years, where he taught pharmacology and pharmacy law and authored more than 100 peer-reviewed manuscripts in neuropharmacology with an emphasis on antidepressant and antipsychotic drugs and drug abuse. He is a three-time recipient of UCONN’s School of Pharmacy teacher of the year award and maintains a continuing interest in pharmacy law, especially in areas involving drugs.
Anna Shurtleff Smith, MPH, BSN-RN
Anna Shurtleff Smith is a graduate of the University of North Texas Health Science Center, School of Public Health, with a community health focus, and Texas Tech University School of Nursing. She has clinical experience in both inpatient and outpatient settings. Anna is passionate about patient education, health literacy, and health communications.
Pamela Sardo, PharmD, BS
Pamela Sardo, PharmD, BS, is a freelance medical writer and licensed pharmacist. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.
Abstract
The drug overdose crisis in the United States began in the 1990s. This crisis was fueled by a growth in opioid prescriptions by healthcare providers and is referred to as the “first wave.” The first wave was followed by a second wave, driven by a rise in heroin use. A third wave followed, which was highlighted by the use of synthetic opioids. Now, a fourth wave has emerged in the opioid overdose crisis. This wave is marked by polysubstance misuse involving opioids (primarily fentanyl) combined with stimulants. These waves have caused a progressively higher number of drug overdose deaths in the United States. However, since late 2023, overdose deaths have steadily declined each month—a strong sign that public health interventions are making a difference and having a meaningful impact. This activity reviews the distinctive features of each wave of the drug overdose crisis, the increasing role of polysubstance misuse in the fourth wave, the emergence of novel substances, and the differences when assessing, diagnosing, and treating opioid and stimulant overdoses and use disorders.
Accreditation Statements
In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation CouncilTM for Continuing Medical Education (ACCME®), the Accreditation Council for Pharmacy Education (ACPE®), and the American Nurses Credentialing Center (ANCC®), to provide continuing education for the healthcare team.
This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credits for learning and change.
Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:
Pharmacists: JA4008424-0000-26-076-H01-P
Credits: 3 contact hour(s) (0.3 CEU(s)) of continuing education credit.
Credit Types:
IPCE Credits - 3 Credits
AAPA Category 1 Credit™️ - 3 Credits
AMA PRA Category 1 Credit™️ - 3 Credits
Pharmacy - 3 Credits
Type of Activity: Knowledge
Media: Computer-Based Training (i.e., online courses)
Estimated time to complete activity: 3 contact hour(s) (0.3 CEU(s)), including Course Test and course evaluation.
Release Date: May 24, 2026 Expiration Date: May 24, 2029
Target Audience: This educational activity is for Physicians, Physician Assistants, and Pharmacists
How to Earn Credit: From May 24, 2026, through May 24, 2029, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Take the “Educational Activity Pre-Test;”
Study the section entitled “Educational Activity;” and
Complete the Educational Activity Post-Test and Activity Evaluation. The Educational Activity Post-Test will be graded automatically. Following successful completion of the Educational Activity Post-Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
CE and CME Credits: Credits for this course will be uploaded to CPE Monitor® for pharmacists and pharmacy technicians. Physicians may receive AMA PRA Category 1 Credit™️ and use these credits toward Maintenance of Certification (MOC) requirements. Physician Assistants may earn AAPA Category 1 CME credits, reportable through PA Portfolio. All learners shall verify their individual licensing board’s specific requirements and eligibility criteria.
Statement of Need
In the current “fourth wave” of the overdose crisis, characterized by widespread co‑use of opioids with stimulants (often contaminated with illicit fentanyl), and emergent novel substances. Polysubstance exposure changes assessment, toxicology interpretation, and acute and long-term treatment plans. Managing complex polysubstance overdoses without standardized, up‑to‑date training on recognition, acute management, and harm‑reduction counseling specific to opioid–stimulant combinations remains a clinical practice dilemma. This educational activity provides updated guidance to improve recognition of co-use, mixed fentanyl–stimulant overdoses, screening, diagnostic accuracy, and acute management practices tailored for coordinated treatment decisions. The goal is to address unmet needs by reviewing overdose trends, clinical implications, and management strategies.
Learning Objectives: Upon completion of this educational activity, participants should be able to:
Explain how polydrug misuse has become the dominant factor in overdose deaths
Discuss the characteristics and health consequences associated with stimulant misuse.
Apply evidence-based strategies for assessing patients with opioid and stimulant use disorders.
Discuss the treatment differences between opioid and stimulant use disorders
Disclosures
The following individuals were involved in planning, developing, and/or authoring this activity: L. Austin Fredrickson, MD, FACP; Gerald Gianutsos, PhD, JD; Anna Shurtleff Smith, MPH, BSN-RN; and Pamela Sardo, PharmD, BS. None of the individuals involved in developing this activity has a conflict of interest or financial relationships related to the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.
© RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Educational Activity Pre-Test
Which change in vital signs after naloxone should most strongly make you suspect hidden stimulant use in addition to fentanyl?
Improved breathing with a calm demeanor
New tachycardia and rising blood pressure
Persistent pinpoint pupils with normal vitals
Immediate return to baseline and request to leave
Treatment regimens for stimulant use disorder (StUD) include
*contingency management (CM), a behavioral intervention, and drug testing to confirm abstinence.
buprenorphine, naltrexone, and methadone, which are FDA-approved medications for StUD.
co-prescribing naloxone with nonpharmacologic music therapy for blood pressure reduction.
providing the patient with a supply of fentanyl test strips and referral to a yoga center to reduce heart rate.
How do cocaine and methamphetamine differ significantly?
Cocaine produces fewer acute, dangerous effects than methamphetamine.
There is no smokable form of methamphetamine, as there is with crack.
Methamphetamine has a much longer duration of action than cocaine.
Cocaine is rarely mixed with opioids.
Educational Activity
It Is No Longer Just an Opioid Problem: Polysubstance Misuse and the Fourth Wave of the Overdose Crisis
Highlights
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Introduction
The drug overdose crisis in the United States began in the 1990s. This crisis was fueled by a growth in opioid prescriptions and is referred to as the “first wave.” Efforts to address this crisis have failed to reduce misuse and death from drug overdose. Instead, a second wave, driven by a rise in heroin use, and a third wave, which was highlighted by the use of synthetic opioids, followed. A fourth wave has emerged in the opioid overdose crisis. Although drug overdose deaths are usually due to the misuse of opioids, the current “fourth wave” of overdose deaths is increasingly characterized by polysubstance misuse, especially with stimulants combined with fentanyl. Novel, recently discovered substances are also appearing in overdose and death cases. This change in the character of drug overdoses requires a change in overdose assessment and treatment responses that are tailored to polysubstance cases. On the positive side, since late 2023, overdose deaths have steadily declined each month—a strong sign that public health interventions are making a difference and having a meaningful impact.
This activity reviews the distinctive features of each wave of the drug overdose crisis and the increasing role of polysubstance misuse in the fourth wave. It also discusses the diagnosis and treatment of opioid and stimulant use disorders.
The First Three Waves of the Drug Overdose Crisis
The modern overdose crisis has occurred in four waves, with different substances playing a predominant role.1 The first three waves, discussed in this section, were marked by distinctive trends in drug use: the first wave was driven by prescription opioids, the second wave by an increase in heroin use, and the third wave by synthetic opioids, such as fentanyl.1 It is important to recognize and review the characteristics of the first three waves because, although they may not be dominant, the misuse of the dominant drugs in those waves continues to cause harm.
The First Wave: Prescription Opioids
Emphasis on Pain Management
The first wave began in 1996 and was largely due to overdose from prescription opioids, fueled by a greater emphasis on treating chronic pain.2 In the 1990s, healthcare providers began prescribing higher amounts of opioid analgesics to address what was perceived at the time to be a widespread problem of undertreated pain.3 Many healthcare advocates and professional organizations supported new standards in the way that pain is acknowledged and managed, including characterizing pain as the “Fifth Vital Sign.”4
In 2000, Congress proclaimed the upcoming decade as the "Decade of Pain Control and Research” as part of the Pain Relief Promotion Act.5 In the act, Congress acknowledged that inadequate pain management for malignant and nonmalignant diseases was a “serious public health problem” and that “in the first decade of the millennium, there should be a new emphasis on pain management and palliative care.”5
The Pain Relief Promotion Act amended the Controlled Substances Act (CSA) to support the concept that alleviating pain or discomfort in the usual course of professional practice is a legitimate medical justification for the dispensing, distributing, or administering of a controlled substance, even if it may increase the risk of overdose.5
In addition, the Drug Enforcement Administration (DEA) amended its rules for prescribing controlled substances in 2007 to allow prescribers to issue multiple prescriptions for a Schedule II controlled substance at a single office visit.5
These policy changes led to substantial increases in opioid prescriptions and resulted in more dependence among patients, greater diversion to non-medical uses, and skyrocketing increases in overdose deaths.6
Efforts to Mitigate the First Wave Opioid Crisis
In response to the developing overdose crisis, opioid prescribing was discouraged, and other steps were taken to deter misuse and diversion.6,7 Efforts to mitigate misuse and diversion included the implementation of prescription drug monitoring programs (PDMP), increasing physician awareness of the appropriate use of opioids along with new prescribing guidelines, legislation to limit the proliferation of pill-mills, development of “abuse-deterrent opioid formulations” (ADOs), and use of opioid use disorder (OUD) treatment plans.7-9 The Centers for Disease Control and Prevention (CDC) established guidelines to help curb the overdose crisis from opioid prescribing.9 The CDC’s guidelines were not universally well-received. The AMA stated that patients needing pain relief were being harmed by “arbitrary restrictions on opioid therapy” recommended by the CDC’s 2016 guidelines.10
These measures were largely successful in reducing opioid prescriptions. The national opioid dispensing rate declined from 2010 to 2015.6 However, from 2010 through 2012, the average duration of an opioid prescription increased to >30 days. The rate of these longer prescriptions stabilized, followed by a substantial decrease in shorter prescriptions (<30 days) after 2012.6 The CDC interpreted this to mean that fewer patients were started on opioids to treat pain after 2012. However, patients already receiving opioids were more likely to continue receiving them.6
The Second Wave: Heroin
The efforts to reduce opioid prescriptions that gave rise to the first wave did see a significant decline in opioid prescriptions, and by 2020, the dispensing rate had fallen to its lowest level in 15 years.7 However, despite these mitigation efforts, total opioid overdose death rates continued to soar, leading to the Second Wave.2,7,8
The second wave began around 2010.2 As prescription opioids became harder to obtain, users turned to other means of obtaining opioids. Some shifted to non-prescription opioids, primarily heroin.2,7 During this period, the heroin supply expanded, and its price dropped, making it more available to users.2,7
The Third Wave: Synthetic Opioids
The third wave started in 2013 and was associated with an increased supply of illicitly manufactured and smuggled synthetic opioids, especially fentanyl and its analogs.2,11 Fentanyl is a powerful mu-opioid receptor agonist that is 75–100 times more potent than morphine.12 Fentanyl was originally introduced more than 50 years ago as an alternative to morphine as an analgesic and anesthetic for surgical use due to its rapid onset, short duration of action, high potency, and limited cardiovascular risks compared to morphine.12 The potential for fentanyl misuse was initially believed to be minimal, but it has emerged as a dangerous recreational substance.12 Although commonly described in the media as a recent phenomenon, fentanyl has been a factor in illicit drug overdose for decades, having been used as an adulterant in street drug supplies since at least 1979.13
The unprecedented growth in overdoses due to fentanyl was driven by users either intentionally seeking the higher potency opioid as their drug of choice or unknowingly using fentanyl, which was added to their preferred drug, most commonly heroin, to improve its rewarding properties and lower production costs.7,11 The current rise in fentanyl is considered to be more a supply rather than a demand-driven event, replacing heroin during a heroin shortage.14 The flow of fentanyl into the U.S., has increased since its rise to prominence in 2014, with newer source countries and transit points emerging in the global supply chain.15 The primary source countries for fentanyl trafficking are China and Mexico, with India also emerging as an important source of precursor chemicals and finished fentanyl powder.15 Other factors that have contributed to the increased use of fentanyl include more efficient methods of synthesis and lax or ineffective regulatory environments in source countries.11,14 Users are also subject to greater risks from the concealment of synthetic opioids in powders sold as heroin or pressed into counterfeit pills.11
In some areas, fentanyl and its analogs have virtually displaced traditional opioids.11 They have become the leading cause of drug overdose deaths, accounting for almost 2/3 of overdose deaths in 2021.11,13 In 2022, an estimated 109,000 drug overdose deaths occurred in the United States.16 Nearly 70% of these involved synthetic opioids other than methadone, and most often the drug was illegally manufactured fentanyl and fentanyl analogs.16
During this same time period, 2020 through 2022, the COVID-19 pandemic disrupted lives through social isolation, loss of economic opportunity, boredom, despair, disruption of normal routines, and political polarization. At the same time, the lockdowns made it more difficult to access treatments, resources, and emergency services that help people suffering from OUD.17,18 Lockdowns and distancing efforts also made it less likely that an individual who overdosed would be discovered and given naloxone in time to prevent lasting injury or death.18 The decreased access to interventions and treatment led some patients to seek new remedies independently, often from unknown, less reliable sellers who may supply contaminated products.17
In addition, COVID-19 mobility restrictions made it more challenging to smuggle illegal drugs into the country, and border restrictions made it harder to move bulkier drugs.19 As a result, smugglers increased their reliance on fentanyl, which, due to its potency, can be transported in small quantities and is easier to traffic by mail.13,19 This helped make fentanyl more available to areas in the U.S., that had not previously been as impacted by the drug.19 Before the pandemic, fentanyl mainly affected urban areas in the Eastern regions of the U.S., where it could be easily mixed with the powdered heroin popular in this region.19
With the end of the pandemic, overdose deaths did not fall as much as may have been expected.20 Factors contributing to the sustained dangers from fentanyl include an expansion in the black-market production and supply of counterfeit prescription drugs containing fentanyl and the increase in concurrent use of other illicit substances.20
The Fourth Wave: Polysubstance Misuse
Historically, drug overdose deaths were usually due to the misuse of opioids; however, the current “fourth wave” of overdose deaths is characterized by polysubstance misuse, especially with stimulants combined with fentanyl.20-22 Increasingly, polysubstance misuse involves novel substances, such as 7-hydroxymitragynine (7-OH), a byproduct of the kratom plant, and bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (BTMPS), an industrial chemical.23-25
Polysubstance use may result from intentional, simultaneous use of multiple substances or the unintentional use of a drug that has been contaminated with another substance.20,22,23 Available evidence suggests intentional co-use contributes substantially to polysubstance exposure, although unintentional exposure due to contamination of illicit drug supplies also remains important.26
The use of multiple substances is now more common and is defining the fourth wave.7 From January 2021 through June 2024, 309,274 people died from overdoses, according to reports received from 49 states and the District of Columbia.27 Of the 309,274 reported overdose deaths, the polysubstance implicated was as follows:27
59.0% involved a stimulant, and 73.0% of these stimulant-involved overdose deaths co-involved opioids (primarily fentanyl14), including 79.1% opioids with cocaine and 68.8% opioids with methamphetamine
14.5% of deaths involved only stimulants
31.2% involved methamphetamine
30.0% involved cocaine
3.8% involved methamphetamine and cocaine
1.6% involved prescription stimulants
0.7% involved synthetic cathinones
3,4-methylenedioxymethamphetamine (MDMA) or methyl- enedioxyamphetamine (MDA) were rarely involved (0.4%).
Polysubstance misuse, which may now involve three or more substances, including novel substances, has changed the landscape of the overdose crisis.23 There may need to be changes in testing, data collection, and treatment.23 For example, some scientists state that the CDC’s reported overdose deaths in this emerging polydrug environment may be incomplete.23 The CDC often uses a 2-drug testing limit, which fails to capture the majority of polysubstance deaths adequately.23 About 75% of these deaths may be incompletely described, and this becomes worse as deaths increasingly involve more drugs or novel drugs that are not being tested.23
The ability to detect novel chemicals and drugs accurately will depend on expanded, comprehensive toxicological testing.23 It may also require changes to ICD-10 coding to allow for newly detected substances.23
Racial and Regional Disparities
There are disparities in overdoses and deaths along racial lines.20,22,28-30 Disparities vary regionally. The upper Midwest (i.e., Minnesota, Wisconsin) and Washington state rank highest in excessive Native overdose deaths; the upper Midwest and Washington, D.C., rank highest in Black overdose deaths.29 White Americans experience the highest percentage of opioid and stimulant overdose deaths in Appalachia, the Rust Belt, and parts of New England. West Virginia, Ohio, Pennsylvania, Kentucky, and Maine consistently report disproportionately high rates of White overdose fatalities.30
Risk Factors for Opioid and Stimulant Use Disorders
Young age, non-rural residency, and mental disorders are risk factors of opioid and polysubstance opioid misuse and overdose.28 An OUD or stimulant use disorder (StUD) is also a risk factor for polysubstance misuse.31
Multiple Substance Use
There are novel substances and many variations when it comes to polysubstance and opioid misuse. This section reviews the more prevalent combinations, as well as some of the emerging high-risk combinations.
Psychostimulants and Opioids
There has been a surge in the simultaneous use of psychostimulants with opioids; more than half of reported psychostimulant overdose deaths in 2019 also involved an opioid.32,33 Studies have shown that there is an overlap between the use of opioids and other substances and that OUD frequently coincides with other substance use disorders.32-36 One study looking at a nationally representative U.S., database found that 90% of individuals with OUD were polydrug users, and over 25% had at least two other substance use disorders along with OUD.35
The surge in overdose deaths has most commonly been observed in individuals using fentanyl with CNS stimulants.11,20 The combination of an opioid with cocaine has long historical roots, traditionally being referred to colloquially as a “speedball.”30 However, the concurrent use of opioids and stimulants has risen markedly, and overdose deaths from the simultaneous use of both agents have been rising since 2015.19 In addition to stimulants, fentanyl combined with benzodiazepines or the veterinary sedative, xylazine (“tranq”), has also driven the trend towards dangerous polysubstance use.37
There are many reasons why drug users may combine other substances with opioids: one drug may enhance the reward or high produced by the other, or a drug may block or reduce the undesirable effects of the other.35 In the case of opioids and psychostimulants, it has been suggested that combined use may establish an equilibrium between the activation produced by the stimulant and the sedation produced by opioids to balance out their effects and allow the user to maintain near-normal functioning.35 Alternatively, the use of both drugs may produce a high with two entirely different, alternating pleasurable sensations.7 However, behind the pleasurable sensations is an increased risk that consuming multiple drugs can lead to unpredictable pharmacological interactions.34
The risk of fatality is greater when stimulants are combined with opioids than when stimulants are used alone.34 Between 2013 and 2019, the rate of drug overdose death increased at a faster rate when both cocaine and opioids were involved compared with cocaine alone.34 From 2009 through 2016, the rate of overdose deaths involving psychostimulants without opioids was higher than the rate involving psychostimulants with opioids. However, this pattern reversed between 2017 and 2019, with higher rates of overdose deaths when both psychostimulants and opioids were involved.34
Stimulants and Heroin
These drug combinations also follow a geographic pattern, with the Northeast region of the U.S., being affected first by an increase in the co-use of stimulants with heroin.7,34 By 2021, all the states in the Northeast had a stimulant as the most common substance co-involved with an opioid; cocaine was the most commonly co-involved substance in seven states, and methamphetamine in two.7 While the highest percentage of opioid-stimulant fatalities was in the Northeast, the West, traditionally a hotbed for stimulant misuse, was the lowest.7
Methamphetamine and Fentanyl Use
Methamphetamine use with other substances is also on the rise.38 Studies show that there is an increase in the use of methamphetamine in individuals with OUD.38 Methamphetamine serves as an opioid substitute, interacts with opioids to create a “synergistic high,” and balances out some of the effects of opioids so the individual can function "normally."38
Epidemiologic data show that there was a 50-fold increase in the methamphetamine mortality rate between 2010 and 2021.39 Moreover, 61% of methamphetamine-associated deaths co-involved heroin or fentanyl.39
Methamphetamines are listed among the two most common stimulants to be misused.40,41 Methamphetamine can be injected, smoked, snorted, or swallowed.41 The initial methamphetamine “rush” is characterized by increased energy and alertness, an elevated positive mood state, and decreased appetite.42 Methamphetamine has a relatively long half-life among psychostimulants (for example, in comparison to cocaine and nicotine), ranging from 8 to 12 hours.42 Deaths from the poly-use of methamphetamines and opioids have disproportionately impacted Native American populations.29
Cocaine and Opioids
Along with methamphetamines, cocaine is the other most common stimulant with high misuse potential.43,44 The rate of drug overdose deaths involving cocaine and opioids increased nearly 450% from 2009 to 2019.43 By 2019, three-quarters of the 15,883 drug overdose deaths involving cocaine also involved one or more opioids.34 In all, fentanyl and stimulants accounted for the largest proportion of overdose deaths in 2021; overdoses in which either fentanyl or a stimulant is involved rose to 84% in 2021 compared with 23% in 2010.45 Non-Hispanic blacks are twice as likely to die from opioids and cocaine as from opioids alone compared with non-Hispanic whites.22
Emerging High-Risk Combinations
The medical community is increasingly focused on novel substances that are complicating polysubstance misuse and treatment.23 Fatal overdoses may now involve three or more substances.23 These include novel stimulants and sedatives (e.g., 7-OH and BTMPS) mixed with fentanyl.23,24,46
Kratom and 7-OH
Kratom and its byproduct 7-OH exhibit potent mu-opioid receptor agonist activity, causing opioid-like effects, including tolerance, dependence, and withdrawal symptoms.46 Products containing kratom or 7-OH are commonly marketed online and may also be sold in smoke shops, vape shops, and gas stations.47,48 These products may contain highly concentrated alkaloids, variable dosing, or contaminants, increasing the risk of toxicity and overdose, particularly when combined with other substances, such as opioids or other CNS depressants.46,49
These products are not approved by the Food and Drug Administration (FDA), and the FDA has issued warning letters advising caution with their use.47,48 Moreover, the FDA recommends that certain 7-OH products be added to the controlled substance schedule under the CSA.47
BTMPS
BTMPS is a hindered amine light stabilizer used primarily to protect plastics, adhesives, films, and coatings from ultraviolet light degradation.49 Since June 2024, it has been detected in 22 states.49 For example, 284 drug product samples tested in Los Angeles and Philadelphia, and 98 (35%) contained BTMPS.24 These samples were collected from drug paraphernalia during specified months in 2024.24 The samples showed a pattern of increasing use. In Los Angeles, the proportion of detected BTMPS per month increased from 0% in June 2024 to 56% in September and 50% in October that same year.24 In Philadelphia, the proportion of detected BTMPS was 25% in June 2024 and 32% the following September.24
BTMPS is an active and potent L-type calcium channel blocker.50 It targets and binds to the same domains that benzodiazepines and phenylalkylamines use.50 BTMPS is shown to be a non-competitive antagonist at nicotinic acetylcholine receptors.50 It is used in its white powder form as an adulterant in drugs, typically opioids, especially fentanyl.50 Its emergence may signal a change in illicit drug manufacturing, or it may be it is being added to dilute more expensive substances.24
Currently, there is insufficient data to ascertain BTMPS’ toxicity in humans.49,50 However, BTMPS acts as a sedative, which can complicate overdose treatment if it is present.51 In addition, BTMPS has led to serious health effects, such as cardiotoxicity and pulmonary injury in animal models.51 Patients with opioid exposure who present with unexpected autonomic or circulatory events may have BTMPS poisoning.51 Patient or drug sample testing for BTMPS may be appropriate, typically as a send-out lab test, as it is not commonly available on routine hospital toxicology screening. There is no known antidotal therapy for BTMPS.51
Prevalence of Drug Overdose
Deaths due to drug overdose continue to be a major public health problem.45 The overwhelming majority of drug overdose deaths resulted from an overdose of an opioid.45,52 In the U.S., recent data indicate that drug overdose deaths involving fentanyl together with stimulants are rapidly becoming the dominant force in the U.S., overdose crisis.14,52 The frequency of overdose fatalities has maintained a steady increase over the past three decades. However, since late 2023, overdose deaths have steadily declined each month—a strong sign that public health interventions are making a difference and having a meaningful impact.53,54
The emerging risk of stimulant misuse and overdose resembles the earlier opioid epidemic since it involves the use of illicit products, largely methamphetamine and cocaine, as well as the non-medical use of prescription medications.14 Healthcare professionals should note that 13.8 million people aged 12 or older misused prescription psychotherapeutic drugs in 2024.55 Prescription opioids were the most commonly misused prescription drug (7.6 million people), followed by tranquilizers or sedatives (4.6 million people), and stimulants (3.9 million people).55
Effects of Co-Using Opioids and Stimulants
Polysubstance use of opioids and stimulants can damage many organs in the body.56-59 Patients who co-use opioids and stimulants have poorer concurrent medical, mental health, and substance use outcomes, as well as a poorer medical history.56 Concurrent mental and physical conditions may be preexisting, exacerbated, or caused by polysubstance use.56-59 The physical and mental impacts can persist even during abstinence.
Psychiatric conditions may include schizophrenia, bipolar disorder, anxiety, depression, and personality disorders.56-59 Chronic physical health conditions are extensive. Some examples include neoplasms, diabetes, hypertension, cardiac diseases, congestive heart failure, chest pain, palpitations, myocardial infarction, cardiomyopathy, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), gastrointestinal dysfunction, end-stage renal disease, and HIV/AIDS.56-61 Subarachnoid hemorrhage may occur within minutes after intranasal insufflation of cocaine (i.e., snorting cocaine).61,62
Because this population may inject these drugs and share needles, they may present with chronic viral infections (e.g., HIV, hepatitis C, invasive bacterial infections, such as skin and soft tissue infections, endocarditis, osteomyelitis, and septic arthritis.58
Use of psychostimulants can also lead to death, including in first-time users; however, stimulants are more likely to produce long-term health consequences related to cardiovascular and neurological damage. Stimulant-related deaths, when they do occur, are usually due to severe alterations in cardiovascular and cerebrovascular function from long-term cumulative exposure to stimulants.63-66
Healthcare Team’s Role in Combatting the Overdose Crisis
There are a number of actions members of a healthcare team may take to combat the overdose crisis, beginning with an assessment by the primary care physician of the risk factors for an overdose, OUD, or StUD.67 There are prophylactic actions, such as co-prescribing naloxone, and long-term treatment plans that may be used.
Diagnosing OUDs or StUDs
Under the DSM-5, an OUD is defined as “a problematic pattern of opioid use leading to clinically significant impairment or distress.”68,69 An StUD is defined as “a pattern of amphetamine-type substance, cocaine, or other stimulant use leading to clinically significant impairment or distress, from mild to severe.”68,70 The DSM-5 also provides criteria that primary care physicians may use when considering a diagnosis of OUD or StUD.68-71 In addition, there are other assessment tools, such as the Rapid Opioid Use Disorder Assessment (ROUDA) and the Rapid Stimulant Use Disorder Assessment to DSM‐5 stimulant use disorder (RSUDA).67 Pharmacists on the healthcare team may also screen patients for OUDs or StUDs.72-74 In the retail pharmacy setting, a pharmacist can review a patient’s electronic health records for a diagnosis of OUD or StUD by the primary care provider, or the pharmacist may see a red flag on the prescription drug monitoring program (PDMP) website.73,74 The pharmacist could also interview and screen patients using a screening tool such as Screening, Brief Intervention, and Referral to Treatment (SBIRT).72-74
Clinical Pearls Polysubstance use is rarely differentiated, which means the healthcare team often does not know what specific drugs a patient is taking. This limits a physician’s ability to develop effective, substance-specific treatment plans.57 In the case of an overdose, patient stabilization, a comprehensive physical assessment, including, if possible, identifying illegal drug use, is important for targeted toxicology testing.57,75 For long-term treatment plans, not all treatment plans are effective against opioids and stimulants.30,76 |
Diagnosing Opioid Intoxication
Opioid intoxication is identified by the classic triad of miosis (excessive constriction of the pupils), respiratory depression, and loss of consciousness.77 Urine tests use morphine as a single calibrator drug. Blood, saliva, sweat, and hair tests may also be used to confirm the diagnosis.75 Interpretation of the test results can be complicated because of test calibration and the different chemical structures of opioids, causing many opioids to escape detection.75 For example, oxycodone requires a ~ 6-fold higher concentration to detect against morphine as the calibrator drug compared to other opioids, and fentanyl and buprenorphine require specific immunoassays as they are very distinct in structure.75 Fentanyl test strips to detect fentanyl are a rapid and inexpensive way to determine whether fentanyl is implicated in an opioid overdose. Results can be obtained within 5 minutes, which can be the difference between life and death.78 A negative test should be read with caution since test strips may not detect more potent fentanyl-like drugs, like carfentanil.78
Diagnosing Stimulant Intoxication
Unlike opioid overdoses, stimulant overdoses are not defined by a single symptom. Instead, they happen when people use a toxic level of a stimulant that produces a range of adverse physical and psychological reactions.79 These events are sometimes referred to as “overamping,” which is distinct from the respiratory depression seen in opioid overdoses.80 Signs of overamping include extreme physical and psychological distress, such as tachycardia (rapid heart rate), high blood pressure, extreme sweating, difficulty breathing, seizures, chest pain, and severe anxiety or paranoia.80
A cocaine intoxication diagnosis is generally made by testing urine specimens for benzoylecgonine, which is an inactive cocaine metabolite.75 Gas chromatography is the gold standard for detecting cocaine metabolites. They can be detected for 5–6 days.75 Long-term use of cocaine can produce positive results for up to 10–22 days after cocaine use.75 Thin-layer chromatography and enzyme-linked immunosorbent assay are widely used for initial screening due to their speed and capacity to handle multiple samples, though they differ in performance characteristics, and are not as sensitive as gas chromatography.75
Methamphetamine can also be detected using a urine test up to about 48 hours after use.75 It can also be detected by hair analysis. A positive methamphetamine screen should be confirmed, as false positives can result. Medications that can cause false-positive results for methamphetamine intoxication include bupropion, phenothiazines, trazodone, labetalol, and ranitidine.75
Table
Comparison of Clinical Features of
Opioid and Stimulant Intoxication
| Clinical Feature | Opioid Intoxication | Stimulant Intoxication |
| Mental Status | Sedation, decreased responsiveness | Agitation, anxiety, paranoia |
| Pupils | Miosis (pinpoint pupils | Dilated or normal pupils |
| Respiratory Status | Respiratory depression | Tachypnea or respiratory distress |
| Heart Rate | Bradycardia or normal | Tachycardia |
| Blood Pressure | Hypotension possible | Hypertension common |
| Skin Findings | Cool, pale skin | Diaphoresis, hyperthermia |
| Major Acute Risk | Respiratory arrest | Cardiac ischemia, stroke, seizure |
| Naloxone Respons | Typically responsive | No direct reversal effect |
| Typical Emergency Management | Naloxone and airway support | Supportive care, cooling, sedation as appropriate |
Co-Prescribing Naloxone
Naloxone is an antidote to opioid overdose. It is an opioid antagonist that can reverse the effects of opioids.81 Increased access to naloxone is an effective way of decreasing the risk of fatal opioid overdoses.82 All patients or families with members at high risk for an overdose should be prescribed and provided with naloxone.82
Naloxone is not effective in treating a stimulant “overdose.”79 However, if there is the potential that opioids have been consumed, either because someone is unconscious and not breathing, or whether drugs were mixed or unknowingly contaminated, naloxone may be lifesaving. Naloxone can reverse the effects of any opioid that might be involved. No harm will be caused by the naloxone if opioids are not involved.79 NARCAN® Nasal Spray and a naloxone prefilled syringe with nasal atomizer (PFS-NA) are devices that can be administered by nonmedical personnel to deliver naloxone during an opioid overdose.82 The healthcare team should collaborate on the question of whether a patient is at risk of an opioid overdose and consider co-prescribing naloxone.
Suspected Overdose
The first step is to call 911. Administer naloxone if an opioid is suspected to be one of the offending drugs.79 The appropriate response to a stimulant overdose depends on the symptoms. A cool wet washcloth and hydration can help lower the patient’s body temperature.63,79 This controls the physical symptoms such as fevers, overheating, and sweating.63,79 Calming techniques that include a dark environment can help minimize psychological symptoms.63,79
Stimulant intoxication can be fatal.63,79,80 If symptoms worsen, or if a person appears to be suffering from extreme overamping, a heart attack, stroke, or seizure, then emergency medical attention is critical. Such serious events can worsen or be caused by previous damage to the cardiovascular system due to chronic stimulant use.63,79,80
Case Report
A published case described a 41-year-old woman presenting with acute onset of quadriparesis after using multiple substances, including pregabalin, methamphetamine, buprenorphine, and alcohol.83 Spinal MRI revealed a longitudinal T2-hyperintense lesion from C2 through T3, with edema in the paravertebral musculature.83 This finding is consistent with deep cervical muscle rhabdomyolysis. Her creatine phosphokinase peak was 16,093 U/L and normalized with corticosteroids and intravenous fluids.83
Despite improvement in the patient’s laboratory values, the patient continued to exhibit limb weakness at discharge.83 This was attributed to venous hypertensive myelopathy, likely caused by deep cervical rhabdomyolysis.83 This case adds to the evidence that, although rare, deep cervical muscle rhabdomyolysis can precipitate venous hypertensive myelopathy through a compartment syndrome-like mechanism. Early MRI evaluation of the spine and surrounding muscle may enable timely diagnosis and improved outcomes in polysubstance-related myelopathy.83
Treatments for Opioid and Stimulant Use Disorders
Treatment regimens for OUDs and StUDs are not the same. Medications are effective for treating OUD but not StUD.30,79 Treatment for StUD focuses on behavioral interventions.
Treatment Regimens for OUDs
In patients with OUD, medications for opioid use disorder (MOUD) have been effective in decreasing drug use.84,85 Treatment for OUD is also known as medication-assisted treatment (MAT), which is an older term to describe this treatment regimen.69 Medication-assisted treatment combined one of three medications (buprenorphine, naltrexone, or methadone) with psychosocial and/or behavioral therapy to help combat an opioid use disorder.69,84
Recently, the Substance Abuse and Mental Health Services Administration (SAMHSA) has proposed replacing the traditional term MAT with “medication for opioid use disorder” (MOUD) because the word "assisted" in MAT implies the medication is a secondary support rather than a primary, necessary treatment.69 This creates a potential “stigma” since the medication part of the treatment (e.g., buprenorphine) may be viewed as “a crutch” that is assisting the patient who is not really sober.86 Calling it MOUD rather than MAT may carry less stigma, since the medication is the primary treatment.83
Others in the healthcare field see the distinction between MAT and MOUD as a difference in emphasis: MAT emphasizes counseling or behavioral therapy alongside medication, whereas MOUD emphasizes medication as the primary, evidence-based treatment.85 A more precise view may be that MOUD is effective, and the evidence supports it as a primary treatment, and MAT may be described as MOUD with concurrent counseling.84,85 Lastly, the acronyms MAT and MOUD will likely continue to be used concurrently because many state and federal regulations still refer to MAT.84
Stimulant use by patients in MOUD can lead to decreased retention in the treatment program.30,76 People in MOUD who subsequently use stimulants may be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use.87 The association appears to be stronger in patients taking buprenorphine compared with those on extended-release naltrexone.87 Given that the current wave of the overdose crisis in the U.S., is marked by poly-use of opioids and stimulants, this issue must be addressed if MOUD is to succeed at curbing opioid use.30
Treatment Regimens for StUDs
In contrast to treating OUDs, there are no FDA-approved medications to treat StUD.88-90 Some medications, such as bupropion and topiramate, are used off-label to treat StUDs.90 The most effective treatment is contingency management (CM), a behavioral intervention that provides tangible rewards to reinforce target behaviors, such as biochemically-verified abstinence (i.e., drug testing).88-90 Drug testing may include testing urine specimens for drug use.75
When CM is not available, other behavioral therapies, such as Cognitive Behavioral Therapy (CBT) or the Matrix Model of addiction treatment program, may be appropriate.90 Cognitive Behavioral Therapy is a psychotherapy in which patients’ negative patterns of thought about themselves and the world are challenged.90 Skills to cope with high-risk situations are developed to change unwanted behavior patterns of drug misuse and to manage psychiatric disorders.90
The Matrix Model is a 16-week behavioral therapy that provides individual counseling, Cognitive Behavioral Therapy (CBT), family education, and social support groups.90 Moderate evidence supports the use of the Matrix Model for the treatment of StUDs.90 The Matrix Model may be more effective in reducing methamphetamine use compared to other standard treatments.90
Patients with StUD often have co-occurring mental and physical health needs.90 Effective management may require interdisciplinary treatment teams. These teams may include physicians with specialties in psychiatry, addiction medicine, or toxicology, nurses, behavioral health professionals, nutritionists, and peer support specialists.90 Care should be coordinated with the patient's participation and consent.90
Patient Case
A 27-year-old man with opioid use disorder arrives at the emergency department after being found somnolent and diaphoretic in a parked car.
What questions can be asked of the companion who brought him to the ED?
His companion reports that he used fentanyl and methamphetamine earlier in the day.
A nurse takes his vital signs. Which signs and symptoms are consistent with the companion statement?
He is tachycardic, hypertensive, agitated, and has shallow respirations. The patient says he just wants to ‘sleep it off.’ The patient is reluctant to accept treatment.
What patient communication can encourage the patient to continue the assessment and treatment planning?
The team explains that mixed opioid-stimulant exposure can produce unpredictable toxicity and that supportive care and naloxone may still be lifesaving if opioids are involved.
What is a possible next step in the treatment plan?
The physician, nurse, pharmacist, and social worker discuss naloxone administration, monitoring, toxicology testing, and evaluation for stimulant-related complications. After stabilization, the team and patient agree on referral for MOUD, contingent management for stimulant use disorder, harm reduction counseling, and follow-up with addiction medicine and behavioral health appointments. The patient agrees to take naloxone home and agrees to the companion's presence during discharge counseling.
Additional Resources
|
|
|
| Certified Poison Control Center | Up-to-date guidance and advice for the treatment of drug overdose | 1-800-222-1222 |
| Substance Abuse and Mental Health Services Administration's (SAMHSA) National Helpline | Free, confidential, 24/7, 365-day-a-year treatment referral and information service (in English and Spanish) for individuals and families facing mental and/or substance use disorders | 1-800-662-HELP (4357) 1-800-662-4357 |
Summary and Key Points
Drug overdose deaths in the United States continue to be a major public health issue. The crisis, mostly due to overdose of opioids, has passed through three previous waves: Prescription drugs, heroin, and illicitly manufactured fentanyl. The most recent wave is largely due to polysubstance misuse, typically opioids mixed with psychostimulants or other depressant drugs.
Deaths involving combinations of fentanyl and stimulants have increased. Simultaneously abusing multiple substances introduces additional dangers for the user. Psychostimulants convey significant cardiovascular risks not normally associated with opioid toxicity.
Individuals consuming multiple substances are at increased risk of overdose, and the non-opioid substances being mixed with fentanyl are not responsive to naloxone, the opioid overdose rescue agent. Some studies suggest patients with combined opioid-stimulant overdose may require higher cumulative naloxone doses or prolonged monitoring compared with opioid-only overdose.
The medical community is increasingly focused on novel substances that are complicating polysubstance misuse and treatment. Fatal overdoses may now involve three or more substances. These include novel stimulants and sedatives (e.g., 7-OH and BTMPS) mixed with fentanyl.
There are important differences between opioid and stimulant use disorders. The concern with opioids is primarily the danger of death from acute overdose, and the corresponding treatment approach is overdose reversal and promoting abstinence. The stimulants, on the other hand, can also cause death but are more likely to produce long-term health consequences related to cardiovascular and neurological damage, and the physical and mental impacts can persist even during abstinence. This necessitates a different approach to treatment and services.
Medications for opioid use disorders are effective for treating OUD but not StUD. In fact, concurrent stimulant use is associated with reduced treatment retention and higher rates of return to non-prescribed opioid use among patients receiving MOUD.
There are no FDA-approved medications to treat StUD. The most effective treatment is CM, a behavioral intervention that provides tangible rewards to reinforce target behaviors, such as biochemically-verified abstinence (i.e., drug testing). Cognitive Behavioral Therapy and the Matrix Model are also among the behavioral interventions that may be appropriate.
In summary, healthcare providers should appreciate that the factors behind the rise in drug overdose deaths continue to be a moving target. They can be effective members of a healthcare team by staying current on future therapies for stimulant use disorder.
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