“Coke in the dope”: The underrecognized complications of a cocaine-adulterated fentanyl supply

Abstract

The opioid crisis, particularly the “fourth wave” involving fentanyl and stimulants, has been responsible for an alarming increase in overdose deaths in the U.S. While fentanyl contamination in cocaine has gained significant attention, the converse—cocaine-adulterated fentanyl—has been largely overlooked despite its health implications. The rise in concurrent cocaine and fentanyl overdose deaths could be attributed to various factors, from intentional polysubstance use to unintentional adulterations. Cocaine-related health issues, may amplify the problem. Four potential pathways for the increased risk of overdose with cocaine-adulterated opioids include enhanced drug reinforcement, potential overdose risk with switching drug samples, altered metabolism of medications used for opioid use disorder, and increased myocardial demand juxtaposed with opioid-induced respiratory depression. With these risks, the importance of drug testing becomes paramount in the unregulated drug market. As polysubstance use overdoses surge, there is an urgent need to understand how drug supplies are changing in order to effectively identify appropriate harm reduction strategies. Specifically, further research is needed evaluating complications of low-level cocaine exposure with chronic/persistent opioid use. The hazards associated with cocaine-adulterated fentanyl emphasize the significance of understanding not just fentanyl’s presence in cocaine but also cocaine’s role in the fentanyl supply.

Introduction

Contamination of the cocaine supply with fentanyl is a major concern due to increasing overdose rates and the growing proportion of cocaine-related overdose deaths. This trend, often referred to as the “fourth wave” of the opioid crisis, shows fentanyl combined with stimulants was responsible for 34,429 deaths in the US in 2021, representing a staggering increase in opioid-stimulant combination deaths by 14,650% since 2010.¹

But the “fourth wave” is not merely fentanyl contamination in the cocaine supply but cocaine contamination in the fentanyl supply. A number of drug testing programs in the US have detected a broad range of substances within submitted samples that were perceived as only containing opioid products, with prevalence of cocaine ranging between 29% to 71%.^2,3 Despite known drug-testing limitations (e.g., distinguishing between contaminated paraphernalia and genuinely adulterated opioids; sampling bias), it would be dangerous to attribute these findings as cross-contamination only. The actual incidence of cocaine adulteration in the fentanyl potentially falls within this range. A potential explanation for the addition of cocaine to fentanyl is that it produces a stimulated sensation that compliments the sedation of an opioid (i.e. adding an “upper” to a “downer”).⁴ While the rise of fentanyl contamination in the cocaine supply has received significant attention, the inverse phenomenon—cocaine-adulterated fentanyl—remains underexplored and poses its own set of concerning health implications.

The exact etiology for the rise in overdose deaths associated with concurrent cocaine and fentanyl use is likely multifactorial. A number of studies evaluate intentional concurrent use of cocaine and opioids (e.g., “speedballs”), and have explored risk of unintentional overdose from fentanyl-adulterated cocaine. Fentanyl adulteration of a cocaine sample could lead to an opioid overdose in an opioid-naïve individual, especially if the presence of fentanyl is unknown.⁵

While overdose deaths may stem from exposure to fentanyl among opioid-naïve individuals using adulterated cocaine, complications from cocaine use itself may also be contributing. Cocaine-related morbidities can include hypertensive emergencies, acute coronary spasms, infective endocarditis, and even impaired pulmonary function in the setting of crack cocaine smoking. We propose four additional pathways that may highlight the potential dangers of cocaine-adulterated in the opioid drug supply.

Behavioral Impact

First, cocaine may increase positive reinforcement of drug use through an increased dopamine “hit,” leading to increased or more frequent use. Animal studies using rhesus monkeys have found that a combination of methadone with cocaine is preferred over either drug alone, and that the combination of heroin with cocaine has synergistic effects with increased reinforcement only when low doses of both drugs are combined. Additional animal models using rats found that acute injections of heroin and cocaine resulted in significant synergistic elevations of dopamine in the nucleus accumbens using in vivo microdialysis.^6,7 These animal studies would suggest then that a fentanyl sample adulterated with a small amount of cocaine would produce a more “desired” effect than an unadulterated sample.

Second, there could be a risk of opioid overdose if there is a shift from insufflating cocaine-adulterated fentanyl to unadulterated fentanyl samples. Persons with regular use of cocaine at the time of buprenorphine pharmacokinetic studies reported significantly greater amounts of daily heroin use prior to buprenorphine treatment and many reported heroin use via insufflation.⁸ Their proposed mechanism for this is that the vasoconstrictive effects of cocaine could contribute to impairment of heroin absorption at the capillary beds which would subsequently lead to a need for an increased use of heroin to avoid withdrawal. These persons would be at risk for an opioid overdose if the cocaine use was reduced or stopped but the amount of opioid use remained the same due to their current tolerance level. This study was not powered enough to evaluate persons with only intermittent cocaine use, but it is possible that this risk is also present in this population as well.

Metabolic Interactions

Third, cocaine has a significant effect on metabolism of medications used in the treatment of opioid use disorder (MOUD), potentially weakening their protective effects. Cocaine is also known to alter the pharmacokinetics of both buprenorphine and methadone in patients with chronic cocaine exposure. One study found that regular cocaine use resulted in statistically significant decreases in buprenorphine plasma concentration compared to those who did not use cocaine regularly, with the proposed mechanisms being induction of CYP3A4 or P-glycoprotein or impaired sublingual absorption of buprenorphine in the setting of cocaine-induced vasoconstriction.⁸ This study found that intermittent cocaine use/exposure was not associated with a statistically significant decrease in buprenorphine plasma concentration, but did have a relatively small sample size and may not have been powered to evaluate intermittent cocaine use. Other studies have also found that chronic cocaine use results in increased methadone clearance/elimination and decreased plasma concentrations, with proposed mechanisms including induction of CYP enzymes, impaired enteral absorption of methadone, and inhibition of renal tubular transportation leading to increased renal clearance.^9,10 The study by McCance-Katz et al also noted that the decrease in methadone plasma concentration due to cocaine appears to be less pronounced compared to that of buprenorphine in the setting of chronic cocaine exposure. The subtherapeutic levels of buprenorphine and methadone may both lead to the same poor outcome: increased opioid withdrawal and cravings with subsequent increases in opioid use.

Fourth, cocaine increases myocardial demand and can exacerbate decreased oxygen supply from opioid-related respiratory depression. By elevating sympathetic tone and catecholamine levels, cocaine increases heart rate, blood pressure, and the myocardial contraction, all increasing the myocardial oxygen demand. Cocaine’s coronary artery constriction and enhanced thrombosis risk ultimately reduces the supply of oxygen to the heart.¹¹ Moreover, one small study demonstrated that cocaine limited cerebral oxygen delivery through significant decreases in absolute whole brain blood flow.¹² These studies highlight a possible pathway of increased overdose risk from the mismatch of cocaine-induced increased metabolic demand and opioid-induced decrease in respiration and oxygen supply. Thus, cocaine-adulterated fentanyl could pose significant risk to patients already at high risk of opioid overdose.

Discussion

These pathways for increased risk of overdose highlight the importance of drug testing in an unregulated drug market. Fentanyl test strips have demonstrated positive changes in overdose risk behaviors.^13,14 Top addiction scientists and health officials have called for greater research and understanding of broader drug testing.¹⁵ While fentanyl test strips are readily available to test a sample of cocaine for possible fentanyl adulteration, no such equipment exists for cocaine for street testing. Additional research is needed to determine if behavior of drug use of individuals using opioids would change if rapid cocaine-testing equipment were available, akin to the behavioral changes observed when fentanyl test strips were introduced for users of heroin.¹³ Prior studies evaluating concurrent exposures of opioids and cocaine typically included individuals who reported chronic/intentional use of cocaine. Further research focusing on the inadvertent intake of cocaine by individuals habitually using opioids can yield a more accurate representation of the health risks associated with unintended, low-dose cocaine exposure.

Given escalating polysubstance use overdoses, there’s an unmistakable urgency for targeted research on drug adulteration and implementing robust harm reduction measures. Greater research on drug testing and ultimate effects on harm reduction strategies can help guide future efforts to protect people who use drugs. The complexities of how individuals use drugs (e.g., polysubstance use may be intentional at times and unintentional adulteration other times) calls for a nuanced understanding of risks in the current unregulated drug supply. As we continue to work towards improving information of the drug supply, researchers, policymakers, and those who use drugs should not overlook the drug contamination in its many forms. Drug testing programs in the US have consistently demonstrated that samples perceived to be solely opioids contain additional adulterants beyond just cocaine. This highlights that the issue extends beyond the contamination of one drug by another. Indeed, the presence of cocaine in fentanyl serves as a stark reminder that the peril may be reciprocal: the danger is not just the “dope in the coke,” but the “coke in the dope.”