Urine Drug Tests Indicate Higher Prevalence of Combined Alcohol and Cocaine Use Compared to Alcohol Together with Cannabis or Amphetamine-A Possible Link to Cocaethylene.

AIM: This retrospective study examined the prevalence of combined ethanol and cocaine use, which produces an enhanced psychoactive effect through formation of the active metabolite cocaethylene, compared to combined use of ethanol and two other common recreational drugs, cannabis and amphetamine, based on urine drug test results. METHODS: The study was based on >30,000 consecutive samples from routine urine drug testing in 2020, and 2627 samples from acute poisonings in the STRIDA project (2010-2016), in Sweden. Drug testing for ethanol (i.e. ethyl glucuronide and ethyl sulfate), cocaine (benzoylecgonine), cannabis (Δ9-THC-COOH) and amphetamine was done by routine immunoassay screening and LC-MS/MS confirmatory methods. Seven samples testing positive for cocaine and ethyl glucuronide were also analyzed for cocaethylene by LC-HRMS/MS. RESULTS: Among routine samples for which testing of ethanol and cocaine had been requested, 43% tested positive for both substances, compared with 24% for ethanol and cannabis and 19% for ethanol and amphetamine (P < 0.0001). Among the drug-related intoxications, 60% of cocaine-positive samples were also positive for ethanol, compared to 40% for cannabis and ethanol and 37% for amphetamine and ethanol. Cocaethylene was detected (range 1.3-150 µg/L) in all randomly selected samples testing positive for ethanol and cocaine use. CONCLUSIONS: These results, which were based on objective laboratory measures, indicated that combined ethanol and cocaine exposure was more prevalent than expected from drug use statistics. This may relate both to the common use of these substances in party and nightlife settings, and the amplified and prolonged pharmacological effect by the active metabolite cocaethylene.

Blood and Plasma Volumetric Absorptive Microsampling (VAMS) Coupled to LC-MS/MS for the Forensic Assessment of Cocaine Consumption.

Reliable, feasible analytical methods are needed for forensic and anti-doping testing of cocaine and its most important metabolites, benzoylecgonine, ecgonine methyl ester, and cocaethylene (the active metabolite formed in the presence of ethanol). An innovative workflow is presented here, using minute amounts of dried blood or plasma obtained by volumetric absorptive microsampling (VAMS), followed by miniaturized pretreatment by dispersive pipette extraction (DPX) and LC-MS/MS analysis. After sampling 20 µL of blood or plasma with a VAMS device, the sample was dried, extracted, and loaded onto a DPX tip. The DPX pretreatment lasted less than one minute and after elution with methanol the sample was directly injected into the LC-MS/MS system. The chromatographic analysis was carried out on a C8 column, using a mobile phase containing aqueous formic acid and acetonitrile. Good extraction yield (> 85%), precision (relative standard deviation, RSD < 6.0%) and matrix effect (< 12%) values were obtained. Analyte stability was outstanding (recovery > 85% after 2 months at room temperature). The method was successfully applied to real blood and plasma VAMS, with results in very good agreement with those of fluid samples. The method seems suitable for the monitoring of concomitant cocaine and ethanol use by means of plasma or blood VAMS testing.

Monitoring of the stability of cocaine and some metabolites in water and oral fluid by a newly developed CE method.

A new CE method was here developed, in order to study the stability of cocaine and some of its metabolites in water and in oral fluid. At first, standard mixtures of cocaine (COC), benzoylecgonine (BE) and cocaethylene (COET) in water were used to study the optimal CE parameters to separate the three compounds. Voltage, sample temperature and pH were investigated, and 25 kV, 25°C and a pH of 4.7 were selected to achieve the best separation. The stability of the three compounds in water and oral fluid was then monitored by applying the previously developed method. Three different storage temperatures (8, 25 and 37°C) were selected and analyses during a week were performed. A decrease of COC and COET peak areas and an increase of BE peak area were observed over time at 25 and 37°C. In addition, in oral fluid, the presence of enzymes and other proteins, and the differences in the molecular structures between COC and COET, caused a stronger degradation of the first compound. Instead, when samples were stored at a low temperature (8°C), the peak areas of the compounds did not vary. Thus, the use of this storage temperature is recommended, above all when sample must be analyzed after a relatively long time.

Metabolomics of cocaine: implications in toxicity.

Cocaine is the most commonly used illicit drug among those seeking care in Emergency Departments or drug detoxification centers. Cocaine, chemically known as benzoylmethylecgonine, is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The pharmacokinetics of cocaine is dependent on multiple factors, such as physical/chemical form, route of administration, genetics and concurrent consumption of alcohol. This review aims to discuss metabolomics of cocaine, namely by presenting all known metabolites of cocaine and their roles in the cocaine-mediated toxic effects.

Genders and the concurrent use of cocaine and alcohol: Pharmacological aspects.

AIMS: Gender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. METHODS: The MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. RESULTS: Besides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. CONCLUSIONS: The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.

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

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.

Cardiovascular Risks of Simultaneous Use of Alcohol and Cocaine-A Systematic Review.

Background: The simultaneous use of cocaine and alcohol is highly prevalent and is associated with high numbers of emergency department admissions, primarily due to cardiovascular complications. Aims: To answer the question of whether the co-use of cocaine and alcohol increases the cardiovascular risk compared to the use of cocaine alone. Method: A systematic review of human studies comparing the cardiovascular risk of co-used cocaine and alcohol with the use of cocaine alone. Results: Despite a higher myocardial workload induced by the co-use of cocaine and alcohol and the potentiation of cocaine's cardiovascular effects by alcohol, the findings on the risk and severity of cardiovascular symptoms due to combined use are inconsistent. However, the co-use of cocaine and alcohol clearly leads to higher mortality. Interestingly, the presence of cocaethylene, a unique metabolite generated only via a pharmacokinetic interaction between alcohol and cocaine, carries an 18- to 25-fold increase over the absence of cocaethylene (cocaine-alone users) in the risk of sudden death and is associated with myocardial injury and cardiac arrest, probably due to the inhibition of cardiac ion channels by cocaethylene. Conclusion: Despite the inconsistency in some of the results, it is concluded that the co-use of cocaine and alcohol poses an additional risk of cardiovascular fatalities compared to the use of cocaine alone.

Cocaethylene cardiotoxicity in emergency department patients with acute drug overdose.

OBJECTIVES: Cocaine use results in over 500,000 emergency department (ED) visits annually across the United States and ethanol co-ingestion is reported in 34% of these. Commingling cocaine with ethanol results in the metabolite cocaethylene (CE), which is metabolically active for longer than cocaine alone. Current literature on the cardiotoxicity of CE compared to cocaine alone is limited and lacks consensus. This study aims to fill this gap in the literature and examine cardiovascular events in cocaine use as confirmed by urine toxicology versus CE exposure. METHODS: This was a secondary data analysis of a prospective cohort study of adult patients with acute drug overdose at two urban tertiary care hospital EDs over 4 years. Patients with positive urinary cocaine metabolites were analyzed, and outcomes were compared between patients with overdose and confirmed presence of cocaine on urine toxicology (cocaine group) and patients with cocaine and ethanol use (CE group). The primary outcome was cardiac arrest. Secondary outcomes included myocardial injury and hyperlactatemia. Data were analyzed using multivariable regression models. RESULTS: We enrolled a total of 199 patients (150 cocaine, 49 CE). Rates of cardiac arrest were significantly higher in the CE group compared to cocaine (6.1% vs. 0.67%, p = 0.048). Cocaine was significantly associated with myocardial injury compared to CE exposure (mean initial troponin 0.01 ng/ml vs. 0.16 ng/ml, p = 0.021), while hyperlactatemia was associated with CE exposure (mean initial lactate 4.1 mmol/L vs. 2.9 mmol/L, p = 0.038). CONCLUSIONS: When compared to cocaine exposure alone, CE exposure in ED patients with acute drug overdose was significantly associated with higher occurrence of cardiac arrest, higher mean lactate concentrations, and lower occurrence of myocardial injury.

A comparison of the reinforcing strength of cocaethylene and cocaine in monkeys responding under progressive-ratio and concurrent choice schedules of reinforcement.

BACKGROUND: Individuals who use cocaine have high rates of co-morbid alcohol use and when ethanol and cocaine are administered concurrently, the metabolite cocaethylene is formed. Cocaethylene is equipotent to cocaine in blocking dopamine reuptake and substitutes for cocaine in drug discrimination studies. However, no previous work has directly compared the reinforcing strength of cocaine to cocaethylene. METHODS: In Experiment 1, three individually-housed adult male rhesus macaques self-administer cocaine under a progressive-ratio (PR) schedule of reinforcement, during daily 4-hr sessions. Under this schedule, the primary dependent variable is the number of injections received, or the break point (BP). Saline, cocaine (0.001-0.3mg/kg/injection) and cocaethylene (0.0003-0.1mg/kg/injection) dose-response curves were determined. In Experiment 2, two female cynomolgus and one rhesus macaque responded under a concurrent schedule of drug (cocaine or cocaethylene) vs. 1.0-g banana-flavored food pellets, during daily 1-hr sessions. RESULTS: Both cocaine and cocaethylene functioned as reinforcers under the PR and concurrent choice schedules of reinforcement. Under the PR schedule, peak BPs were not significantly different, nor were ED50 values on the ascending limb, suggesting that cocaethylene has equal reinforcing strength and potency to cocaine. Under the concurrent drug-food choice procedure, cocaethylene was also equally potent to cocaine. CONCLUSIONS: Under two schedules of reinforcement designed to assess reinforcing strength, cocaethylene and cocaine were equipotent and of equal reinforcing strength. Because cocaethylene has a longer duration of action, it is important for studies designed to evaluate treatments for cocaine use to also consider the effects of these interventions on cocaethylene.

Cocaethylene: When Cocaine and Alcohol Are Taken Together.

Cocaine is taken frequently together with ethanol and this combination produces a psychoactive metabolite called cocaethylene which has similar properties to the parent drug and may be more cardiotoxic. Cocaethylene has a longer half-life than cocaine, so that people who combine cocaine and ethanol may experience a longer-lasting, as well as more intense, psychoactive effect. Cocaethylene is the only known instance where a new psychoactive substance is formed entirely within the body. Although known to science for decades, cocaethylene has not been extensively studied and even its metabolic pathways are not entirely elucidated. Like its parent drug, cocaethylene blocks the reuptake of dopamine and increases post-synaptic neuronal activity; the parent drug may also block reuptake of serotonin as well. Cocaethylene has been studied in animal models in terms of its pharmacology and its potential neurological effects. Since the combination of cocaine and alcohol is commonly used, it is important for clinicians to be aware of cocaethylene, its role in prolonging or intensifying cocaine intoxication, and how it may exacerbate cocaine-induced cardiovascular disorders. Most cardiac-related risk assessment tools do not ask about cocaine use, which can prevent clinicians from making optimal therapeutic choices. Greater awareness of cocaethylene is needed for clinicians, and those who use cocaine should also be aware of the potential for polysubstance use of cocaine and ethanol to produce a potentially potent and long-lasting psychoactive metabolite.

Cocaethylene, simultaneous alcohol and cocaine use, and liver fibrosis in people living with and without HIV.

BACKGROUND: The simultaneous consumption of cocaine and alcohol results in the production of cocaethylene (CE) in the liver, a highly toxic metabolite. Prior research suggests that cocaine use contributes to liver disease and its concomitant use with alcohol may increase its hepatotoxicity, but studies in humans are lacking. We evaluated the role of cocaine, its simultaneous use with alcohol, and CE on liver fibrosis. METHODS: We performed a cross-sectional analysis of the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was determined via self-report, urine screen, and blood metabolites, using liquid chromatography with tandem mass spectrometry. Hazardous drinking was determined with the AUDIT-C and liver fibrosis with the Fibrosis-4 Index (FIB-4). RESULTS: Out of 649 participants included in this analysis, 281 (43.3%) used cocaine; of those, 78 (27.8%) had CE in blood. Cocaine users with CE had higher concentrations of cocaine metabolites in blood and were more likely to drink hazardously than cocaine users without CE and cocaine non-users. Overall, cocaine use was associated with liver fibrosis. CE in blood was associated with 3.17 (95% CI: 1.61, 6.23; p = 0.0008) times the odds of liver fibrosis compared to cocaine non-users, adjusting for covariates including HIV and HCV infection. The effect of CE on liver fibrosis was significantly greater than that of cocaine or alcohol alone. CONCLUSIONS: CE is a reliable marker of simultaneous use of cocaine and alcohol that may help identify individuals at risk of liver disease and aid in the prevention of its development or progression.

Tyrosine nitration of a humanized anti-cocaine mAb differentially affects ligand binding of cocaine and its metabolites.

Tetranitromethane was used to selectively modify tyrosine residues of a humanized anti-cocaine mAb (h2E2), under development for the treatment of cocaine use disorders. The effect of mild tyrosine nitration on the affinity of cocaine and two high affinity cocaine metabolites, cocaethylene and benzoylecgonine, was assessed using differential scanning fluorimetry to measure ligand affinities via ligand-induced thermal stabilization of the mAb antigen binding region. Nitrated tyrosine residues were identified by mass spectral analysis of thermolysin peptides. One objective was to understand the binding affinity differences observed for these three ligands, which are not explained by the published crystal structure of the h2E2 mAb Fab fragment co-crystalized with benzoylecgonine, since the carboxylic acid of benzoylecgonine that is esterified to form cocaine and cocaethylene is not in contact with the mAb. Importantly, the binding affinity of the cocaine metabolite benzoylecgonine was not decreased by mild nitration, whereas the binding affinities of cocaine and cocaethylene were decreased about two-fold. These ligands differ only in the substituent attached to the carboxylate moiety of the compound, with benzoylecgonine having an unesterified carboxylate, and cocaine and cocaethylene having methyl and ethyl esters, respectively, at this position. The results are consistent with nitration of light chain tyrosine residue 34, resulting in a less favorable interaction with cocaine and cocaethylene carboxylate esters, while not affecting binding of benzoylecgonine. Thus, light chain Tyr34 residue may have molecular interactions with cocaine and cocaethylene not present for benzoylecgonine, leading to the observed affinity differences for these three ligands.

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse.

An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol- and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use. This article is part of the special issue on Neurocircuitry Modulating Drug and Alcohol Abuse.

Hydroxycocaines as Metabolic Indicators of Cocaine Ingestion.

Hydroxycocaines in hair were investigated with many hundreds of head and body hair samples. All samples were washed by a published extensive aqueous method prior to confirmation by LC-MS/MS. Concentrations, percent of cocaine, and ratios of para- and meta-hydroxycocaines to ortho-hydroxycocaine are presented. Hydroxycocaines as percent of cocaine did not appear to be affected by cocaine concentrations, but were shown to increase with cocaethylene concentrations. Stability of hydroxycocaines over a year of ambient storage was demonstrated. Ortho-hydroxycocaine was shown to be formed by exposure of cocaine-positive hair to peroxide, while para- and meta-hydroxycocaines were not. Presence of para- or meta-hydroxycocaine at > 0.05% of cocaine is proposed as indicating ingestion of cocaine. This indicator prevents black hair from being more likely interpreted as positive for ingestion than lighter colored hair.

Alcohol and Cocaine Combined Substance Use on Adult Hypothalamic Neural Stem Cells and Neurogenesis.

Many advancements have been made over the years looking at the individual and combined effects of drugs of abuse on the brain, with one key area of research focusing on the effects on neurogenesis. An integral part of fetal brain development and, later, maintenance in the adult brain, neurogenesis occurs in three main regions: subventricularzone of the lateral ventricles (SVZ), subgranularzone of the dentate gyrus (SGZ), and the tanycyte layer in the hypothalamus (TL). We will review current literature on combined drugs of abuse and their effect on adult neurogenesis. More specifically, this review will focus on the effect of combining cocaine and alcohol. Additionally, the tanycyte layer will be explored in more depth and probed to look at the neurogenic properties of tanycytes and their role in neurogenesis.

Cocaine and Alcohol Co-Ingestion-Induced Severe Rhabdomyolysis With Acute Kidney Injury Culminating in Hemodialysis-Dependent End-Stage Renal Disease: A Case Report and Literature Review.

Cocaine toxicity is associated with several organ dysfunctions, including acute kidney injury (AKI). Rhabdomyolysis is the most likely mechanism that mediates AKI, and associated alcohol co-ingestion can amplify the situation. AKI, if severe, can result in end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). All patients with cocaine intoxication should be screened for rhabdomyolysis and AKI along with testing for other drug toxicity, including alcohol. Aggressive measures should be taken to treat the underlying cause that contributes to AKI, and the patients need to be educated about this severe condition. Our patient is a unique case where cocaine and alcohol co-ingestion led to severe rhabdomyolysis, AKI, and subsequently developed ESRD requiring ongoing hemodialysis (HD). He was on daily cocaine and alcohol co-ingestion for seven days and subsequently developed AKI with oliguria from rhabdomyolysis. His creatine kinase (CK) was significantly elevated to 141974 IU/L, and his serum creatinine was 11 mg/dl. Despite aggressive intravenous hydration, his kidney function did not improve, and he ended up needing HD for more than one year despite abstaining from cocaine.

Ligand binding to a humanized anti-cocaine mAb detected by non-reducing SDS-PAGE.

Monoclonal antibodies are very useful tools in experimental biology, as well as being valuable and effective therapeutic drugs. They can be targeted against proteins with varied functions, or against small molecules of interest to both researchers and clinicians, such as drugs of abuse, including cocaine. Since there is no currently FDA approved pharmacological treatment for cocaine abuse, our laboratory has developed an anti-cocaine mAb for the treatment of cocaine use disorders. This humanized anti-cocaine antibody, named h2E2, has been thoroughly characterized both functionally and structurally, in preparation for the start of clinical development. We previously showed that this mAb could be characterized by sequential thermal unfolding of antibody domains using non-reducing SDS-PAGE. We also demonstrated that ligand-induced protein stabilization can be used to quantitatively measure cocaine and cocaine metabolite binding to the h2E2 mAb, utilizing differential scanning fluorimetry. Here, we demonstrate the utility of non-reducing SDS-PAGE for the qualitative assessment of binding of cocaine and some of its metabolites, both to the intact mAb, as well as to fragments containing the antigen binding site (Fab and F(ab')2 fragments). These results clearly show a ligand concentration dependence of the stabilization of the cocaine binding domain in non-reducing SDS-PAGE, as well as visually differentiating the relative binding affinities of various cocaine metabolites. Thus, non-reducing SDS-PAGE is a simple and widely available technique that is useful as a measure of binding of cocaine and its metabolites to the h2E2 mAb, and it is likely that this technique will also be applicable to other small molecule-directed mAbs.

Determination of Cocaine and Metabolites in Dried Blood Spots by LC-MS/MS.

Cocaine is one of the most common illegal drugs in Europe and other parts of the world. It is mainly metabolized to benzoylecgonine and ecgonine methyl ester but also to minor metabolites such as norcocaine and meta-hydroxy-benzoylecgonine. If ethanol is consumed simultaneously, cocaethylene is formed. Dried blood spots (DBS) are a minimally invasive sampling technique producing easy-to-ship specimens and have garnered increasing attention in forensic and clinical contexts in recent years. We hereby present a liquid chromatography/tandem mass spectrometry-based (LC-MS/MS) method for the quantification of cocaine, benzoylecgonine, ecgonine methyl ester, norcocaine, meta-hydroxy-benzoylecgonine, and cocaethylene in DBS.

Data on ethyl glucuronide and cocaethylene concentrations in the hair of cocaine users.

We present data on ethyl glucuronide and cocaethylene concentrations from the hair of cocaine users. Head hair from 64 subjects, previously tested for cocaine, cocaethylene, benzoylecogonine and anhydroecgonine methyl ester (AEME), were subsequently analysed for Ethyl Glucuronide (EtG). Samples were prepared by solid phase extraction and analysed using gas chromatrography coupled to tandem mass spectrometry. The dataset is made available to allow analysis of possible correlation between cocaethylene and ethyl glucuronide or between other metabolites presented in the data.

The importance of considering polysubstance use: lessons from cocaine research.

BACKGROUND: Polysubstance use (PSU) is prevalent among individuals with substance use disorders, but the vast majority of preclinical substance use research has focused on individual substances in isolation. Cocaine has been prevalent in the repertoire of persons who use more than one illicit substance. METHODS: We conducted a meta-analysis combining results from literature searches and secondary data analyses to estimate the prevalence of simultaneous and concurrent cocaine + alcohol and cocaine + cannabis use among cocaine users. We next summarized the small body of literature on behavioral, cognitive and neurobiological consequences of cocaine PSU across species, with a focus on alcohol and cannabis. Finally, we used systematic literature searches to assess the extent to which human and animal studies on the neurobiological consequences of cocaine include PSU subjects. RESULTS: The estimated prevalence of simultaneous and concurrent alcohol use among human cocaine users was 74% and 77%, respectively. The estimated prevalence of simultaneous and concurrent cannabis use among cocaine users was 38% and 64%, respectively. Consumption of alcohol or cannabis with cocaine enhances subjective responses to cocaine, concomitant with changes in cocaine metabolism that increase blood cocaine levels, and, in the case of alcohol, produce the psychoactive metabolite cocaethylene. There is also consistent evidence for neurobiological effects of cocaine + alcohol combinations. However, animal PSU research with cocaine lags behind human research. CONCLUSION: Based on the prevalence and known consequences of PSU, consideration of PSU in both human and animal research is vital for understanding patterns of substance use.