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Abstract

Introduction

Cocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong.

Methods

This was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data.

Results

We analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01–0.77; p = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings.

Conclusions

In contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.

Keywords

Cocaine cocaethylene ethanol poisoning emergency department

Introduction

Cocaine misuse is increasingly popular worldwide.¹ In Hong Kong, it has superseded methamphetamine and cannabis and has become the most frequent substance of abuse among newly reported drug users since 2022² and all drug users since 2023 (except heroin).^2,3 Cocaine is commonly used with ethanol.^4,5 In the United States, the estimated number of emergency department visits related to cocaine and ethanol was 165,731 in 2022.⁵

Despite its common occurrence, the effects of ethanol co-ingestion on acute cocaine toxicity remain a subject of debate in the literature. Ethanol increases the intranasal bioavailability of cocaine by vasodilating effects on nasal mucosa, causing increased cocaine absorption and plasma concentrations through snorting, cocaine “high” ratings, and heart rate.^6,7 Such a combination also results in hepatic transesterification, which converts approximately 17% of cocaine to cocaethylene.^8–10

Cocaethylene is an active metabolite of cocaine with a similar blocking effect on dopamine reuptake,¹¹ but its half-life is 1.5 times longer than cocaine.^12,13 A recent study by Shastry et al. reported an increased risk of cardiac arrest in emergency department patients with cocaine and ethanol co-ingestion and attributed the increased risk to cocaethylene.¹⁴ However, blood concentrations of cocaine, cocaethylene, or any metabolites appear to have poor correlations with the severity of clinical presentations.^15,16

Clarifying the toxic effects of combining cocaine and ethanol has important implications for clinical management and public education. However, the current literature is limited by conflicting evidence and a lack of isolated analyses of cocaine and ethanol exposure in real-world patients with acute cocaine toxicities. The inclusion of co-ingestants other than cocaine in the analysis might have confounded the findings.¹⁴ Poison center-based studies and studies on the Asian population are lacking, casting doubt on the generalizability of previous study results. To address these limitations, we aimed to compare the clinical presentations and outcomes in patients with co-exposure to cocaine and ethanol and patients with cocaine use alone in a predominantly Chinese population in Hong Kong.

Methods

Study design

This study was a retrospective observational study that included consecutive episodes of acute cocaine toxicity reported to the Hong Kong Poison Control Center between 1 January 2010 and 22 January 2023. The study was approved by the Institutional Review Board of The University of Hong Kong and the corresponding research ethics committees of the Hospital Authority (HA; reference no. UW 22-544, UW20-597, KC/KE-22-0138/ER-4, and KC/KE-20-0270/ER-2) with a waiver of consent in view of the retrospective analysis of de-identified data. We reported the study findings according to the Strengthening the Reporting of Observational Studies in Epidemiology statement.¹⁷

Study setting and data source

The Hong Kong Poison Control Center, the data source for this study, is the only poison center in Hong Kong. It provides round-the-clock phone consultations on poisoning cases to local healthcare professionals and receives voluntary reports of poisoning from all public emergency departments. It maintains an electronic database, the Poison Information and Clinical Management System, which contains information on all consultations and reports received. Clinical data from consultations and reporting are entered into the electronic database by staff trained in clinical toxicology. The severity and outcome of each case are routinely classified with reference to the America’s Poison Centers’ National Poison Data System into five categories: no effect, mild effect, moderate effect, major effect, or death. The relationship between exposure to the poison and the clinical outcome is graded as definite, probable, possible, not related, or undetermined/not applicable.¹⁸ Data quality is assured by verification by senior clinical toxicologists, regular internal audits, and team discussions of individual cases. The Poison Information and Clinical Management System contains territory-wide data that are representative of the pattern of poisonings presented to all public emergency departments in Hong Kong.

Study population

All cases with self-reported cocaine use or clinical presentation of acute cocaine toxicity in emergency departments and a positive urine test for cocaine exposure were included in this analysis. A positive urine test was defined as the detection of cocaine or its metabolites in urine by either bedside immunoassay or hospital laboratory tests based on liquid chromatography–mass spectrometry or high-performance liquid chromatography. The exclusion criteria were 1) cocaine exposure not confirmed by urine immunoassays and/or laboratory toxicology tests, 2) co-exposure to other recreational drugs, 3) intentional overdose of other medications, 4) co-ingestion of other medications, 5) unexplained presence of other therapeutics in urine without prior documented use or with suspicion of overdose, except for known adulterants or cutting agents for cocaine, such as levamisole and phenacetin,¹⁹ 6) malicious exposure, 7) clinical presentation not explained by cocaine, 8) unrelated cases, 9) body packing, and 10) non-emergency department cases.

Data collection

We identified eligible cases from the Poison Information and Clinical Management System by a poison code search and retrieved their electronic medical records through the Hospital Authority Clinical Management System. Since the Hong Kong Poison Control Center and all public hospitals are under the Hospital Authority administration in Hong Kong, clinical researchers have access to the electronic medical records of all reported cases. The Clinical Management System contains all medical records of every patient treated in public hospitals in Hong Kong, including clinical data, laboratory results, and outcomes. Two research assistants collected data from these records independently in parallel using a standardized data entry manual after lectures and data entry training. The first two authors cross-checked all data, determined the inclusion of individual cases, and resolved all discrepancies in data entry. Data collected from the Clinical Management System included demographics (age, sex and ethnicity), poison data (history of drug exposure and ethanol consumption, urine immunoassay and laboratory test results, and the first blood ethanol concentration), clinical presentations (including vital signs, occurrence of agitation and drowsiness), and complications (including acute myocardial injury, acute kidney injury, rhabdomyolysis, seizure, cardiac arrest, and intensive care unit admission).

Definitions

Ethanol exposure was confirmed by a detectable blood ethanol concentration on presentation. Patients without laboratory confirmation were assumed not having been exposed to ethanol. We defined patient’s past physical health as “unremarkable” in the absence of any chronic physical co-morbidities, such as hypertension, after reviewing clinical records. Myocardial injury was defined as an elevated cardiac troponin value above the 99^th percentile of the upper reference limit, with a rise and fall of the value, according to the Fourth Universal definition of Myocardial Infarction.²⁰ Acute kidney injury was defined according to the Kidney Disease: Improving Global Outcomes guidelines, as an increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 h, or by ≥ 1.5 times from baseline within 7 days or urine volume < 0.5 mL/kg/hour for 6 h²¹ Rhabdomyolysis was defined as a creatine kinase level > 1000 IU/L in the absence of myocardial infarction/creatine kinase elevation with cardiac etiology, chronic renal failure, or neuromuscular disease with myopathy.²² We dichotomized the clinical outcomes into serious (patients with a National Poison Data System outcome rating of moderate, major, or death) and non-serious (patients with a National Poison Data System outcome rating of mild or no effect).

Primary and secondary outcomes

The primary outcome was the occurrence of a serious clinical outcome during the index emergency department presentation. Secondary outcomes included the occurrence of cardiac arrest, seizure, acute myocardial injury, acute kidney injury, and rhabdomyolysis.

Data analysis

The Statistical Package for Social Sciences version 28.0 was used to analyze the data. Independent sample t-tests, non-parametric tests, chi-squared tests, and Fisher’s exact tests were used to compare differences in clinical presentations and outcomes between the cocaine and ethanol co-exposure group and the cocaine-only group, as appropriate. Multivariable logistic regression was performed to evaluate the effects of co-exposure to cocaine and ethanol compared to cocaine alone on clinical outcomes, after adjusting for age, sex, ethnicity, route of cocaine administration, and past physical health status. The results were expressed as number (percentage), median (interquartile range), odds ratio, and the respective 95% confidence intervals.

We conducted the same comparative analysis for the subgroups of patients with blood ethanol concentrations measured and the respective laboratory tests required for defining individual secondary outcomes performed, such as creatine kinase for rhabdomyolysis. A two-tailed p-value smaller than 0.05 was considered statistically significant.

Results

During the study period, 485 episodes of acute poisoning that involved cocaine were identified from the Poison Information and Clinical Management System and 376 episodes were excluded according to the pre-defined exclusion criteria as detailed in Figure 1. The majority of the cases were excluded due to co-exposure to other recreational drugs. In total, 109 patients were included for analysis, of whom 74 had their blood ethanol concentrations checked and 20 had confirmed ethanol exposure with a mean blood ethanol concentration of 29.3 mmol/L (1350 mg/L). All of the included patients had drug screens, either by urine immunoassays or hospital laboratory tests. Most of the included patients were Chinese (68%) and more than half had unremarkable past physical health. Significantly more patients in the ethanol co-exposure group used cocaine by insufflation compared to the cocaine-only group (75% vs 36%, p = 0.02). The demographics and clinical characteristics are summarized in Table 1.

Figure 1.

Patient flow diagram. * The sum of individual drugs was greater than the total because of polysubstance misuse.

Table 1.

Patient demographics, clinical characteristics, and outcome.

	Total N = 109	Cocaine and ethanol co-exposure N = 20	Cocaine only N = 89	p-value
Age—median (IQR), year	29.0 (25.0–34.0)	29.5 (23.8–33.8)	28.0 (25.0–34.5)	0.79^a
Sex (%)
Female	31 (28)	3 (15)	28 (32)	0.14^c
Male	78 (72)	17 (85)	61 (69)
Chinese Ethnicity (%)	74 (68)	10 (50)	64 (72)	0.06^c
Unremarkable past physical health (%)	63 (58)	14 (70)	49 (55)	0.22^c
Route of cocaine exposure
Insufflation	47 (43)	15 (75)	32 (36)	0.02^c
Inhalation	29 (27)	0 (0)	29 (33)
Oral	12 (11)	1 (5)	11 (12)
Intravenous	2 (2)	0 (0)	2 (2)
Others	4 (4)	1 (5)	3 (3)
Unknown	15 (14)	3 (16)	12 (14)
Blood ethanol concentration checked	74 (68)	20 (100)	54 (61)	0.001^c
ED triage vital signs
SBP—Median (IQR), mmHg	138 (121–157)	138 (122–151)	138 (120–157)	0.81^a
DBP—median (IQR), mmHg	83 (72–96)	80 (70–93)	84 (73–97)	0.36^a
Pulse—median (IQR), beats per minute	98 (89–122)	103 (85–122)	98 (90–122)	0.92^a
RR—median (IQR), breath/min	18 (16–20)	18 (16–24)	18 (16–20)	0.16^a
SpO₂—median (IQR), %	98 (97–99)	98 (97–99)	98 (96–99)	0.66^a
Temperature—median (IQR), °C	36.8 (36.3–37.3)	36.8 (36.0–37.3)	36.8 (36.4–37.4)	0.33^a
Clinical features (%)
Agitation	24 (22)	4 (20)	20 (23)	> 0.99^b
Drowsiness	12 (11)	4 (20)	8 (9)	0.23^b
Chest pain	18 (17)	3 (15)	15 (17)	> 0.99^b
ECG features—median (IQR), ms
QRS duration	96 (86–103)	100 (88–107)	96 (86–103)	0.24^a
Corrected QT interval	433 (413–448)	436 (413–449)	433 (413–447)	0.66^a
NPDS outcome (%)
Death	0 (0)	0 (0)	0 (0)	0.10^c
Major effect	10 (9)	0 (0)	10 (11)
Moderate effect	24 (22)	2 (10)	22 (25)
Minor effect	73 (67)	17 (85)	56 (63)
No effect	2 (2)	1 (5)	1 (1)
Primary outcome
Serious outcome	34 (31)	2 (10)	32 (36)	0.02^c
Secondary outcomes (%)
Cardiac arrest	2 (2)	0 (0)	2 (2)	> 0.99^b
Seizure	9 (8)	0 (0)	9 (10)	0.21^b
Acute myocardial injury	9 (8)	1 (5)	8 (9)	> 0.99^b
Acute kidney injury	10 (9)	0 (0)	10 (11)	0.20^b
Rhabdomyolysis	16 (15)	0 (0)	16 (18)	0.04^b

Abbreviations: DBP, diastolic blood pressure; ED, emergency department; ICU, intensive care unit; IQR, interquartile range; NPDS, National Poison Data System; RR, respiratory rate; SBP, systolic blood pressure.

^anon-parametric test.

^bFisher’s exact test.

^cChi square test.

The emergency department triage vital signs did not differ significantly between the cocaine and ethanol co-exposure group and the cocaine-only group. There were slightly fewer patients with agitation and more with drowsiness in the co-exposure group, but the differences did not reach statistical significance. The proportions of patients with chest pain were similar in both groups. One patient in the co-exposure group developed acute myocardial injury compared with eight in the cocaine-only group, but the difference was not statistically significant. None in the co-exposure group developed cardiac arrest, seizure, acute kidney injury or rhabdomyolysis. As for rhabdomyolysis, the difference between the two groups was statistically significant (0% vs 18%, p = 0.04).

Overall, two patients (10%) in the co-exposure group and 32 (36%) in the cocaine-only group had a serious clinical outcome (i.e., a National Poison Data System outcome rating of moderate or above). In the multivariable analysis, confirmed ethanol co-exposure was associated with a significantly lower odds of serious outcomes, after adjusting for age, sex, ethnicity, route of cocaine administration, and past physical health status (adjusted odds ratio 0.09, 95% confidence interval 0.01–0.77, p = 0.03). In the subgroup analysis of 74 patients with blood ethanol concentrations measured, univariate and multivariable analyses showed similar findings in the primary outcome and occurrence of rhabdomyolysis (Table 2 and Supplemental Table 1). Other secondary outcomes did not differ significantly between the groups in the subgroup analyses (Supplemental Table 1).

Table 2.

Univariate and multivariable analysis of the effect of co-exposure to cocaine and ethanol on serious clinical outcome.

	Cocaine and ethanol co-exposure N	Cocaine only N	Un-adjusted OR (95% CI)	p Value	Adjusted OR^a (95% CI)	p Value
Serious outcome
All patients	20	89	0.20 (0.04–0.91)	0.04	0.09 (0.01–0.77)	0.03
Subgroup analysis^b	20	54	0.15 (0.03–0.71)	0.02	0.07 (0.01–0.62)	0.02

^aAdjusted for the patient age, sex, ethnicity, route of cocaine administration, and past physical health status.

^bAnalysis of 74 patients with blood ethanol concentration measured.

Discussion

Co-exposure to cocaine and ethanol was significantly associated with fewer serious outcomes compared to cocaine alone, after adjusting for age, sex, ethnicity, route of cocaine administration, and past physical health status, and fewer cases of rhabdomyolysis in the whole cohort and subgroup analyses. None of the patients with cocaine and ethanol co-exposure had cardiac arrest, seizure, or acute kidney injury, although the differences between the two groups did not reach statistical significance.

Cocaine is an addictive stimulant that inhibits the reuptake of dopamine, norepinephrine, and serotonin, increasing their concentrations at post-synaptic receptors and producing sympathomimetic effects. Cocaine intoxication is a frequent cause of drug-related deaths, which are believed to be related to its cardiotoxicity. Cocaine can cause myocardial infarction by coronary artery vasoconstriction, accelerating atherosclerosis, activating platelet aggregation, and blocking sodium and potassium channels causing arrhythmias.²³ When consumed with ethanol, cocaine has been reported to be more lethal than cocaine alone in patients with severe coronary artery disease.²⁴ Notably, Shastry et al. reported an increased risk of cardiac arrest in emergency department patients with cocaine and ethanol co-consumption compared to those with cocaine use only.¹⁴

In contrast to the previous studies, we did not observe a higher risk of cardiac arrest in patients with co-consumption of cocaine and ethanol compared to cocaine use alone. The discrepancies in these observations can be explained by differences in study methodology. The findings reported by Escobedo et al. were based on a case-control study on forensic cases with coronary artery disease,²⁴ which might not be applicable to younger emergency department patients. In the study by Shastry et al., 90% and 88% of the co-exposure group and cocaine-only group, respectively, had co-ingestions including opioids, cannabinoids, antidepressants, and antipsychotics,¹⁴ which might have confounded the study results. In addition, the number of cardiac arrests in their study was small, leading to a wide 95% confidence interval. The causes of cardiac arrests were not reported and causes other than cocaine could be possible. In our study, the effects of cocaine and ethanol were isolated. We believe that our findings can be more directly attributed to cocaine or its combination with ethanol.

There has been no consensus on the underlying mechanism that explains the reported increased cardiotoxicity of combined cocaine and ethanol use. In canine models, Parker et al. showed that ethanol and cocaethylene reduced cocaine clearance, which may enhance its cardiotoxicity.²⁵ Henning et al. and Uszenski et al. demonstrated a synergistic effect of cocaine and ethanol in depressing myocardial function.^26–28 Ethanol does not enhance cocaine-induced coronary vasoconstriction²⁸ but attenuates the rebound of myocardial depression and myocardial blood flow due to cocaine.²⁹ As for cocaethylene, it has a more potent negative inotropic³⁰ and sodium channel blocking effects than cocaine in in vitro studies.³¹ In dogs, cocaethylene has a similar cardiotoxicity to cocaine but is less toxic than ethanol plus cocaine.^26,27 At high concentrations, cocaethylene decreases myocardial function, slows cardiac conduction, and is arrhythmogenic but its cardiotoxicity does not seem to be mediated by coronary blood flow reduction.²⁹ Wilson et al. reported an association between the peak serum cocaethylene concentrations and a dose-dependent reduction in cardiac function³² and prolonged myocardial depression.³³ In human volunteer studies, the combination of cocaine and ethanol consistently led to a greater increase in heart rate compared with cocaine or ethanol alone.^7,34,35 However, the doses of cocaine and ethanol used in animal and human volunteer studies might not represent the doses used by drug users.

The finding by Shastry et al. that patients with co-exposure had a lower risk of acute myocardial injury despite the higher odds of cardiac arrest is also counterintuitive.¹⁴ We did not identify a higher occurrence of acute myocardial injury or cardiac arrest in the co-exposure group in our cohort. Patel et al. reported one case of torsades des pointes after cocaine and ethanol co-ingestion in the absence of other QT-prolonging agents.³⁶ However, we did not observe significant differences in the QRS duration and corrected QT interval between the cocaine-only and co-exposure group in our cohort, indicating that the impact of co-exposure on cardiotoxicity remains uncertain.

Based on human volunteer studies, the euphorigenic effect after co-consumption of cocaine and ethanol varies, with some studies reporting enhanced euphoria with the combination and cocaethylene^9,35 and others reporting less euphoria with cocaethylene.^12,13 One possible explanation of our findings is that less cocaine might have been consumed in the co-exposure group to achieve a similar euphoric effect, leading to a lower risk of cardiotoxicity and cardiac arrest. The drug use patterns of patients with co-exposure and cocaine-only users might also be different. Cocaine-only users are more likely regular users who may use a higher dose compared to co-exposure users who consume cocaine and alcohol when socializing. The route of cocaine administration was also different between the groups, with significantly more insufflation in the co-exposure group. While ethanol may increase cocaine absorption through snorting by vasodilating effects on nasal mucosa,⁷ we observed a lower odd of serious outcomes in the co-exposure group. In the absence of dose information, it is difficult to attribute the observed difference in outcome to the route of cocaine administration alone.

Another possible explanation is genetic polymorphisms in drug metabolism. In our study, Chinese ethnicity constituted 50.0% and 71.7% in the co-exposure and cocaine-only groups, respectively. Little is known about the genetic polymorphisms of carboxylesterase-1, but there is growing evidence that minor genetic variations in this enzyme can affect drug metabolism and drug-drug interactions.^37,38 As for ethanol, the rate of metabolism is mainly determined by alcohol dehydrogenase and cytochrome P450 2E1. Its metabolite, acetaldehyde, is metabolized by aldehyde dehydrogenase. The ADH1B*2 gene for alcohol dehydrogenase and the ALDH2*2 gene for aldehyde dehydrogenase are more frequently found in Chinese populations. While the former marginally increases alcohol dehydrogenase activity on ethanol, the latter inactivates the aldehyde dehydrogenase metabolism of acetaldehyde. Either gene increases acetaldehyde accumulation after alcohol consumption, which reduces alcohol intake due to the undesirable effects of acetaldehyde.³⁹ When cocaine and ethanol are consumed, a lower amount of alcohol intake reduces their combined toxic effects and cocaethylene production. In our study, the mean blood ethanol concentration in the co-exposure group (1350 mg/L) was considerably lower than that reported by Shastry et al. (1528 mg/L).¹⁴ However, it is still not clear how genetic polymorphisms in cocaine, ethanol, and cocaethylene metabolism in Chinese and the differences in blood ethanol concentrations may affect clinical outcomes.

In this study, rhabdomyolysis was less frequent in the co-exposure group in the whole cohort and subgroup analyses. Rhabdomyolysis has been reported in 24%–33% of cocaine users.^40,41 Cocaine accounts for 30% of all rhabdomyolyses presenting to the emergency department⁴² and 33% of patients with cocaine-associated rhabdomyolysis develop acute renal failure.⁴³ The mechanisms of cocaine-associated rhabdomyolysis include vasoconstriction leading to muscular ischemia, direct myocyte toxicity, hyperpyrexia, increased muscle activity from agitation or seizure, prolonged immobilization, compartment syndrome, and trauma.^44,45 The risk factors specific to cocaine users are not well understood,⁴⁰ but age is associated with an increased risk.⁴¹ Our finding is consistent with the study by Vanek et al., which showed significantly less rhabdomyolysis (defined as a creatine kinase concentration > 500 IU/L) in emergency department patients with co-exposure to cocaine and ethanol. However, the difference was no longer significant when trauma patients were excluded and a creatine kinase cut-off at 1000 IU/L was used.⁴⁶ In our study, more patients in the co-exposure group were drowsy at presentation and none had a seizure. In addition to our postulation that ethanol co-ingestion might reduce the amount of cocaine intake needed to achieve euphoria, the sedative effect of ethanol may lead to less psychomotor agitation and rhabdomyolysis.

Strengths and limitations

The strengths of this study include the exclusion of co-ingestants, territory-wide poison center data, and multivariable analysis to adjust for confounding factors. Our study contributes data from a prominently Asian population to the literature. However, given the high prevalence of polysubstance use with cocaine, our sample size was inevitably small after the exclusion of co-ingestants. The small sample size limited the statistical power and might not be large enough to pick up rare complications of cocaine use that lead to cardiac arrest, such as aortic dissection. Caution is advised in interpreting the findings. Spectrum bias might also exist when lethal poisoning cases were not sent to the emergency department. Our study was also limited by the voluntary basis of reporting poisoning cases to the Hong Kong Poison Control Center and missing data in medical records. Since not all suspected poisoning cases undergo standard toxicology tests and blood ethanol concentration measurements in Hong Kong, we could only assume patients who were not tested for ethanol had a non-detectable blood ethanol concentration in the whole cohort analysis. However, the adjusted odds ratio of serious outcomes remained lower in the subgroup analysis with complete data. A larger sample size is needed to improve the robustness of the results. Furthermore, we were not able to reliably determine the time, quantity, or order of cocaine and ethanol consumption, which may impact the quantity of cocaethylene formed after co-exposure.⁴⁷ Finally, measurement of serum cocaine and cocaethylene concentrations are not available in public hospitals in Hong Kong, limiting our ability to evaluate their effects and interplay on acute toxicity.

Conclusion

Compared to cocaine alone, cocaine with ethanol co-consumption was apparently not associated with a higher risk of cardiac arrest and other serious outcomes as previously reported in a predominantly Chinese population. Rhabdomyolysis was also less common in patients with co-exposure. However, given the small sample size after exclusion of co-ingestants, caution is advised when interpreting the findings. Future prospective multicenter studies with a larger sample size may help to clarify the real-world risks of cocaine and ethanol co-consumption.

Supplemental Material

Supplemental Material - Comparing the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone

Supplemental Material for Comparing the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone by Kwun Lok Cheung, Rex Pui Kin Lam Chi Keung Chan, Man Li Tse, Matthew Sik Hon Tsui and Timothy Hudson Rainer by Human & Experimental Toxicology

Footnotes

Acknowledgments

The authors would like to thank Ms Crystal Tsz Yu Tang and Mr Michael Chun Kai Lau for their help in data collection and the staff in the Hong Kong Poison Control Center for their help in data retrieval.

Author contributions

(1) KLC and RPKL conceived and designed the study, (2) KLC and RPKL acquired the data, (3) KLC and RPKL analyzed and interpreted the data, (4) KLC drafted the manuscript, and (5) RPKL, CKC, MLT, TSHM, THR critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article

Ethical statement

ORCID iD

Rex Pui Kin Lam

Data availability statement

The participants of this study did not give written consent for their data to be shared publicly and the research ethics committees did not grant permission to share data with a third party. Supporting data is only available upon reasonable request to the authors and additional permission from the research ethics committees.*

Supplemental Material

Supplemental material for this article is available online.

References

World drug report 2023 [Internet]. Vienna: United Nations Office on Drugs and Crime. Available from: https://www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2023.html. [Accessed 2023 Aug 23].

Central Registry of Drug Abuse . Hong Kong: Narcotics division, security bureau. The Government of the Hong Kong Special Administrative Region, 1986 https://www.nd.gov.hk/en/introduction.html. [Accessed 2023 Aug 7].

Drug abuse and drug situation in Hong Kong in 2022 (with photos) [Internet]. Hong Kong: The Government of the Hong Kong Special Administrative Region; 2023.Available from: https://www.info.gov.hk/gia/general/202303/27/P2023032700298.htm. [Accessed 2023 Aug 7].

Supervía

Ibrahim-Achi

Miró

Red de estudio de drogas en Urgencias Hospitalarias en España REDUrHE , et al. Impact of co-ingestion of ethanol on the clinical symptomatology and severity of patients attended in the emergency department for recreational drug toxicity. Am J Emerg Med 2021; 50: 422–427. DOI: 10.1016/j.ajem.2021.08.046.

Substance Abuse and Mental Health Services Administration . Drug abuse warning network: findings from drug-related emergency department visits. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, 2023. Available from: https://store.samhsa.gov/product/drug-abuse-warning-network-findings-drug-related-emergency-department-visits-2022/pep23-07-03-001#.

Perez-Reyes

Jeffcoat

. Ethanol/cocaine interaction: cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects. Life Sci 1992; 51(8): 553–563. DOI: 10.1016/0024-3205(92)90224-d.

McCance-Katz

Price

McDougle

, et al. Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene. Psychopharmacology (Berl) 1993; 111(1): 39–46. DOI: 10.1007/BF02257405.

Brzezinski

Abraham

Stone

, et al. Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine. Biochem Pharmacol 1994; 48(9): 1747–1755. DOI: 10.1016/0006-2952(94)90461-8.

Harris

Everhart

Mendelson

, et al. The pharmacology of cocaethylene in humans following cocaine and ethanol administration. Drug Alcohol Depend 2003; 72(2): 169–182. DOI: 10.1016/s0376-8716(03)00200-x.

10.

Perez-Reyes

. The order of drug administration: its effects on the interaction between cocaine and ethanol. Life Sci 1994; 55(7): 541–550. DOI: 10.1016/0024-3205(94)00747-0.

11.

Hearn

Flynn

Hime

, et al. Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter. J Neurochem 1991; 56(2): 698–701. DOI: 10.1111/j.1471-4159.1991.tb08205.x.

12.

Perez-Reyes

Jeffcoat

Myers

, et al. Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine. Psychopharmacology (Berl) 1994; 116(4): 428–432. DOI: 10.1007/bf02247473.

13.

Hart

Jatlow

Sevarino

, et al. Comparison of intravenous cocaethylene and cocaine in humans. Psychopharmacology (Berl) 2000; 149(2): 153–162. DOI: 10.1007/s002139900363.

14.

Shastry

Manoochehri

Richardson

, et al. Cocaethylene cardiotoxicity in emergency department patients with acute drug overdose. Acad Emerg Med 2023; 30(2): 82–88. DOI: 10.1111/acem.14584.

15.

Blaho

Logan

Winbery

, et al. Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED. Am J Emerg Med 2000; 18(5): 593–598. DOI: 10.1053/ajem.2000.9282.

16.

Signs

Dickey-White

Vanek

, et al. The formation of cocaethylene and clinical presentation of ED patients testing positive for the use of cocaine and ethanol. Am J Emerg Med 1996; 14(7): 665–670. DOI: 10.1016/S0735-6757(96)90085-6.

17.

von Elm

Altman

Egger

STROBE Initiative , et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370(9596): 1453–1457. DOI: 10.1016/S0140-6736(07)61602-X.

18.

Gummin

Mowry

Beuhler

, et al. 2020 annual report of the American association of poison control centers’ national poison data System (NPDS): 38th annual report. Clin Toxicol 2021; 59(12): 1282–1501. DOI: 10.1080/15563650.2021.1989785.

19.

Laposchan

Kranenburg

Van Asten

. Impurities, adulterants and cutting agents in cocaine as potential candidates for retrospective mining of GC-MS data. Sci Justice 2022; 62(1): 60–75. DOI: 10.1016/j.scijus.2021.11.004.

20.

Thygesen

Alpert

White

Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction . Universal definition of myocardial infarction: kristian thygesen, Joseph S. Alpert and harvey D. White on behalf of the Joint ESC/ACCF/AHA/WHF task force for the redefinition of myocardial infarction. Eur Heart J 2007; 28(20): 2525–2538. DOI: 10.1093/eurheartj/ehm355.

21.

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group . KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2(1): 1–138, DOI: 10.1038/kisup.2012.1.

22.

Stahl

Rastelli

Schoser

. A systematic review on the definition of rhabdomyolysis. J Neurol 2020; 267(4): 877–887. DOI: 10.1007/s00415-019-09185-4.

23.

Phillips

Luk

Soor

, et al. Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options. Am J Cardiovasc Drugs 2009; 9(3): 177–196. DOI: 10.1007/BF03256574.

24.

Escobedo

Ruttenber

Anda

, et al. Coronary artery disease, left ventricular hypertrophy, and the risk of cocaine overdose death. Coron Artery Dis 1992; 3(9): 853–858. DOI: 10.1097/00019501-199209000-00012.

25.

Parker

Williams

Laizure

, et al. Effects of ethanol and cocaethylene on cocaine pharmacokinetics in conscious dogs. Drug Metab Dispos 1996; 24(8): 850–853.

26.

Henning

Wilson

. Cocaethylene is as cardiotoxic as cocaine but is less toxic than cocaine plus ethanol. Life Sci 1996; 59(8): 615–627. DOI: 10.1016/0024-3205(96)00227-5.

27.

Henning

Wilson

Glauser

. Cocaine plus ethanol is more cardiotoxic than cocaine or ethanol alone. Crit Care Med 1994; 22(12): 1896–1906.

28.

Uszenski

Gillis

Schaer

, et al. Additive myocardial depressant effects of cocaine and ethanol. Am Heart J 1992; 124(5): 1276–1283. DOI: 10.1016/0002-8703(92)90412-O.

29.

Wilson

Malik

Willson

. Cocaine and ethanol: combined effects on coronary artery blood flow and myocardial function in dogs. Acad Emerg Med 2009; 16(7): 646–655. DOI: 10.1111/j.1553-2712.2009.00443.x.

30.

Bai

Otsu

Islam

, et al. Direct cardiotoxic effects of cocaine and cocaethylene on isolated cardiomyocytes. Int J Cardiol 1996; 53(1): 15–23. DOI: 10.1016/0167-5273(95)02504-9.

31.

Crumb

Clarkson

. Cocaethylene, a metabolite of cocaine and ethanol, is a potent blocker of cardiac sodium channels. J Pharmacol Exp Therapeut 1994; 271(1): 319–325.

32.

Wilson

Henning

Suttheimer

, et al. Cocaethylene causes dose-dependent reductions in cardiac function in anesthetized dogs. J Cardiovasc Pharmacol 1995; 26(6): 965–973. DOI: 10.1097/00005344-199512000-00017.

33.

Wilson

Jeromin

Garvey

, et al. Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse. Acad Emerg 2001; 8(3): 211–212. DOI: 10.1111/j.1553-2712.2001.tb01296.x.

34.

Higgins

Rush

Bickel

, et al. Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans. Psychopharmacology (Berl) 1993; 111(3): 285–294. DOI: 10.1007/BF02244943.

35.

Foltin

Fischman

. Ethanol and cocaine interactions in humans: cardiovascular consequences. Pharmacol Biochem Behav 1988; 31(4): 877–883. DOI: 10.1016/0091-3057(88)90399-1.

36.

Patel

Opreanu

Shah

, et al. Cocaine and alcohol: a potential lethal duo. Am J Med 2009; 122(1): e5–6. DOI: 10.1016/j.amjmed.2008.09.017.

37.

Laizure

Herring

, et al.

The role of human carboxylesterases in drug metabolism: have we overlooked their importance?

Pharmacotherapy 2013; 33(2): 210–222. DOI: 10.1002/phar.1194.

38.

Geshi

Kimura

Yoshimura

, et al. A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity. Hypertens Res 2005; 28(9): 719–725. DOI: 10.1291/hypres.28.719.

39.

Zakhari

. Overview: how is alcohol metabolized by the body? Alcohol Res Health 2006; 29(4): 245–254.

40.

Welch

Todd

Krause

. Incidence of cocaine-associated rhabdomyolysis. Ann Emerg Med 1991; 20(2): 154–157. DOI: 10.1016/s0196-0644(05)81215-6.

41.

O’Connor

Padilla-Jones

Gerkin

, et al. Prevalence of rhabdomyolysis in sympathomimetic toxicity: a comparison of stimulants. J Med Toxicol 2015; 11(2): 195–200. DOI: 10.1007/s13181-014-0451-y.

42.

Fernandez

Hung

Bruno

, et al. Factors predictive of acute renal failure and need for hemodialysis among ED patients with rhabdomyolysis. Am J Emerg Med 2005; 23(1): 1–7. DOI: 10.1016/j.ajem.2004.09.025.

43.

Roth

Alarcón

Fernandez

, et al. Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988; 319(11): 673–677. DOI: 10.1056/NEJM198809153191103.

44.

Nolte

. Rhabdomyolysis associated with cocaine abuse. Hum Pathol 1991; 22(11): 1141–1145. DOI: 10.1016/0046-8177(91)90267-s.

45.

Gitman

Singhal

. Cocaine-induced renal disease. Expet Opin Drug Saf 2004; 3(5): 441–448. DOI: 10.1517/14740338.3.5.441.

46.

Vanek

Dickey-White

Signs

, et al. Concurrent use of cocaine and alcohol by patients treated in the emergency department. Ann Emerg Med 1996; 28(5): 508–514. DOI: 10.1016/s0196-0644(96)70114-2.

47.

Jones

. Forensic drug profile: cocaethylene. J Anal Toxicol 2019; 43(3): 155–160. DOI: 10.1093/jat/bkz007.

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