Enhanced and Prolonged Euphoria during Co-Use of Alcohol and Cocaine: A Narrative and Integrative Review

Abstract

Introduction

Alcohol and cocaine are frequently used simultaneously, with alcohol typically consumed prior to cocaine. Qualitative studies indicate that this combination enhances and prolongs euphoria compared to cocaine alone. The aim of this study was to collect quantitative data that were published several decades ago, but have never been integrated.

Methods

A narrative and integrative review was conducted to collect and synthetize research data from quantitative controlled human studies on the mechanisms responsible for enhanced and prolonged euphoric sensations during co-use of alcohol and cocaine compared to cocaine alone. A total of 1,012 unique studies were retrieved via Medline (PubMed), Embase, PsycInfo, and Google Scholar of which 24 studies published between 1987 and 2011 met the eligibility criteria.

Results

The current narrative and integrative review shows that the co-use of alcohol and cocaine potentiates and prolongates cocaine’s euphoric effects. First, when alcohol is used prior to oral or intranasal cocaine, it inhibits cocaine metabolism, resulting in higher peak plasma levels (+18–52%) and increased bioavailability (+15–40%) of cocaine. Second, alcohol plus cocaine generates cocaethylene (12–34% conversion) which, compared to cocaine, induces a similar or somewhat less intense but more prolonged euphoria. Third, in contrast to cocaine, cocaethylene selectively inhibits dopamine reuptake resulting in higher synaptic dopamine levels, which may explain its greater reinforcement compared to cocaine.

Conclusion

Co-use of alcohol and cocaine enhances and prolongs the subjective and reinforcing effects of cocaine. Although this may be perceived as an efficient way of drug use, it also poses serious cardiovascular risks.

Introduction

Cocaine may be used concurrently (i.e., on separate occasions) or simultaneously (i.e., on the same occasion) with alcohol. The latter is considered particularly harmful as it may lead to synergic effects with increased risks [1]. Of polysubstance use-related emergency department visits in 2023 in the USA, 15.7% (256,849 cases) involved cocaine, of which 49.6% resulted from co-ingestion of alcohol and cocaine [2] mainly due to cardiovascular complications [3].

Alcohol and cocaine are frequently used together [4–7], with alcohol being mostly consumed prior to cocaine [8, 9]. Cocaine powder users tended to use cocaine and alcohol concurrently, while crack users tended to use alcohol at the end of crack-using sessions [10]. Large surveys from Europe and the USAA indicate a high prevalence of recent cocaine use, with a substantial proportion of these users also engaging in frequent or heavy alcohol consumption [11, 12]. For instance, a meta-analysis estimated that up to 74% (range 24–98%) of cocaine users in the USA also consumed alcohol simultaneously [13]. Combined use of alcohol and cocaine has also been reported in the general population [14] and among individuals attending party and nightlife venues [15, 16]. Furthermore, about 70% of European adolescents reported that their first use of cocaine was under the influence of alcohol [17]. Similarly, the prevalence of alcohol use among cocaine-dependent subjects in both community and drug treatment settings was 84–89% [18, 19].

Of particular interest is the metabolization of cocaine to cocaethylene (CE). CE is a unique metabolite as it is only formed when cocaine and alcohol are used simultaneously [20–22] provided that alcohol is consumed prior to cocaine [23]. CE appears to induce an euphoric effect comparable to that of cocaine and demonstrates greater selectivity for dopaminergic activity than cocaine (cf. Results). Common reasons for the popularity of the simultaneous use of cocaine and alcohol, as reported in qualitative studies, include the mitigation of anxiety and depression feelings associated with cocaine use [13], alteration of the state of consciousness, controls of cravings, reduction of drug expenditure, and management of discomfort and unpleasant emotions. In addition, this combination is reported to enhance sexual, physical, and social functioning, and, finally, to facilitate tapering or cessation of cocaine use [24, 25]. In these qualitative studies, alcohol is also reported to be used to sober up and to attenuate the “coming down” from a cocaine binge [26, 27]. Finally, enhancement and prolongation of a cocaine “high” are often reported as reasons for co-using alcohol and cocaine [28].

Here, we present a review of quantitative data on the effects of co-use of alcohol and cocaine (COC). Although most of these studies were published several decades ago, previous reviews have addressed only selective parts of these data and were, therefore, not able to fully integrate the different aspects [13, 28–30]. The exception is a recent, but valuable paper summarizing the effects of the co-use of several stimulatory substances with a rather general description of the effects of the COC [31]. The current narrative and integrative review is, therefore, the first to collect and integrate all data from quantitative controlled human studies in detail on the different mechanisms underpinning the enhanced and prolonged cocaine “high” following the COC, which may indirectly increase the risk of various side effects.

Methods

The study protocol for this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD420261337853 and conducted (no date filters applied; last search on the March 12, 2026) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Information Sources and Search Strategy

The following databases were searched: Medline (PubMed), Embase, PsycInfo, and Google Scholar. The databases were searched using a predefined list of terms organized into five categories: terms relating to simultaneous use, alcohol-related terms, and terms relating to cocaine and CE. Boolean operators were used to combine these terms to ensure a precise search strategy. When review articles were identified, referenced studies meeting all inclusion criteria for this review were also included as part of the evidence base. PubMed and Google Scholar together have been shown to capture approximately 93% of the published literature on a given biomedical search question [32]. In the PRISMA flowchart (cf. Fig. 1), records retrieved via Google Scholar are presented separately because they were found via full-text searches and may include relevant reports (gray literature).

Fig. 1.

Prisma flow diagram.

Eligibility Criteria

Eligible studies were required to examine the COC in human participants or investigated the inhibition of monoamine transporters for dopamine transporter (DAT), serotonin transporter (SERT), and noradrenaline transporter (NET) by cocaine or CE. The latter studies were included as an important (secondary) add-on to the human studies to provide complementary mechanistic evidence. Outcome variable had to include either (a) subjective experiences (or related outcomes, e.g., euphoria, “high,” drug liking, good drug effect, or well-being), (b) parameters of bioavailability (e.g., C_max, area under the curve [AUC], and elimination half-life), or (c) data on inhibition of DAT, SERT, and NET expressed as IC₅₀-value or K_i-values. Studies focusing solely on toxicological endpoints, such as suicidality, cardiovascular risks, and sudden death, were excluded. The papers were required to describe the dose and route of administration of both alcohol and cocaine (and CE, when appropriate) and to include valid and objective methods for measuring outcome variables. Finally, all included papers had to have undergone peer review.

Selection of Eligible Studies

Retrieved records were screened independently by two reviewers (author 1 and 2) in two rounds, guided by a standardized inclusion checklist outlining the inclusion and exclusion criteria. When disagreement arose, the reviewers discussed the record until agreement was reached. If no agreement could be reached, the suitability of the study for inclusion was evaluated in a separate session during which both reviewers systematically reviewed the inclusion checklist point by point until consensus was achieved.

A total of 1,189 studies were identified in the initial search, and 1,012 unique articles remained after removal of duplicates. These 1,012 studies were subsequently screened based on title and abstract to determine eligibility according to the inclusion and exclusion criteria. In a second round, 19 studies were deemed eligible after full screening. In addition, five further relevant studies were identified through the reference lists of included papers or via Google (Scholar) using appropriate keywords, resulting in a total of 24 eligible studies. Figure 1 presents the PRISMA flowchart for the identification, screening, and inclusion of studies. See online supplementary material for the search string and PRISMA checklist.

Results

Quantitative Data on Euphoric Sensations

Simultaneous Use of Cocaine and Alcohol Compared to Use of Cocaine Alone

To describe the primary subjective goal for their use of cocaine, most recreational users in qualitative studies used the terms “euphoria” or “high”, while others use qualifications like “well-being”, “good effects,” and “feeling good” which we regarded as largely overlapping (less strong) proxies of these effects. Respondents in qualitative studies have reported that the combination of alcohol and cocaine produces more pleasurable effects, i.e., an augmented subjective cocaine “high.” Importantly, quantitative data from controlled human behavioral experiments, summarized in Table 1, have also demonstrated this augmented effect. Acute administration of alcohol to human subjects prior to cocaine consistently increased and prolonged the positive subjective effects (euphoria) induced by cocaine.

Table 1.

Euphoric sensations following COC compared to COC alone in controlled human behavioral experiments

Study design	Alcohol dose	Cocaine dose	Effect of combined use	Reference
Double-blind crossover RCT in 9 healthy individuals	1 g/kg p.o.	100 mg (intranasal)	Higher subjective ratings of “good effects” and “feeling good” in alcohol + COC vs. COC alone	Farré et al. [33]
Double-blind crossover RCT in 8 healthy individuals	0.8 g/kg p.o.	100 mg (intranasal)	Higher ratings of euphoria, “high” and well-being in alcohol + COC vs. COC alone	Farré et al. [34]
Crossover double-blind RCT in 10 healthy individuals	0.5 and 1.0 g/kg p.o.	100 mg (intranasal)	Pretreatment with alcohol increases choice for COC over alternative monetary reinforcer [F(2, 12) = 4.4, p = 0.04)	Higgins et al. [35]
Single-blind crossover RCT in 11 healthy individuals	0.85 g/kg p.o.	1.25 and 1.9 mg/kg (intranasal)	Higher ratings of COC “high”; (F(1, 10) = 16.41 p = 0.002) for low dose and (F(1, 10) = 6.24, p = 0.03) for high dose COC	Perez-Reyes and Jeffcoat [36]
Single-blind crossover RCT in 6 healthy individuals, cocaine HCI	0.85 g/kg p.o.	1.25 and 1.9 mg/kg (intranasal)	Cocaine dose-dependently increased ratings of “high” (F(1, 5) = 8.67, p = 0.03). However, alcohol given 30 min after cocaine snorting did not increase this response	Perez-Reyes [23]
Double-blind crossover RCT in 10 healthy individuals	1 g/kg p.o.	0.3, 0.6, and 1.2 mg/kg (i.v. for 15 min)	Higher rating of drug liking and good drug effect following alcohol + 1.2 mg/kg of COC (p < 0.04) vs. COC alone	Harris et al. [21]
Double-blind RCT in 6 healthy individuals in six sessions, approx. 1 week apart	1 g/kg p.o.	2 mg/kg p.o., 1 mg/kg i.v. or 200 mg smoked	Higher rating of cocaine intoxication (p < 0.05) when administered orally, but no difference following cocaine i.v. or smoking	Herbst et al. [37]
Double-blind RCT in 6 healthy individuals	1 g/kg p.o.	2 mg/kg intranasal	Higher rating of euphoria in combined alcohol + COC vs. COC alone [F = 9.10, df = 6.33, 165, p < 0.001]	McCance-Katz et al. [38]
Double-blind RCT in subjects meeting DSM-IV criteria for COC dependence and alcohol abuse	1 g/kg p.o. at 0 min and 0.12 g/kg p.o. at 60 min	1 mg/kg intranasal dosed at 0, 30, 60, and 90 min	Higher for COC “high” (p < 0.002) and “feel good” (p < 0.04) in alcohol + COC vs. alcohol alone	McCance-Katz et al. [39]
Double-blind RCT in 17 subjects who met diagnostic criteria (DSM-IV) for COC dependence and alcohol abuse	1 g/kg p.o. at 0 min and 0.12 g/kg p.o. at 60 min	1 mg/kg intranasal dosed at 0, 30, 60, and 90 min	Higher rating for “feel good” in alcohol + COC relative to COC alone (p = 0.027) or alcohol alone (p = 0.025)	McCance-Katz et al. [40]
Double-blind, crossover RCT in 10 healthy subjects	0.1 or 0.5 g/kg p.o.	0.6 mg/kg cocaine i.v.	Higher rating for COC “high” for alcohol + COC vs. COC alone (p = 0.02)	Mannelli et al. [41]

The results in Table 1 consistently show that COC significantly enhances subjective effect measures such as “good effects” and “feeling good” compared to alcohol alone or cocaine alone. For instance, in a placebo-controlled, single-blind, crossover RCT, eleven healthy subjects ingested 0.85 g/kg alcohol 15 min before intranasal cocaine administration (1.25 and 1.9 mg/kg) which resulted in a significant increase in ratings of cocaine “high” [36]. In a later study by Harris et al. [21] the combined use of alcohol and cocaine produced dose-dependent increases and prolongation of feelings of euphoria compared with the use of either substance alone [21]. Likewise, the subjective perception of intoxication (“high”) after the administration of alcohol and cocaine was more pronounced compared to cocaine alone (0.6 mg/kg i.v.) [41]. In this study, the increased intensity and duration of the “high” were supported by a correlated increase in EEG indices of intoxication. Similar results were obtained in patients dependent on both cocaine and alcohol. For instance, in a double-blind randomized trial, McCance-Katz et al. [39] compared subjective effects of cocaine, alcohol, and their combined use in patients dependent on both cocaine and alcohol. Greater euphoria and increased perception of well-being were reported in the cocaine + alcohol condition relative to cocaine alone. Using the same experimental design, similar results were later obtained by the same group [40]. Herbst et al. [37] observed higher ratings of cocaine intoxication (47 ± 35 vs. 18 ± 22; p < 0.05) following oral administration, but no difference following i.v. administration or smoking. Using a contingency management design in cocaine-using individuals, alcohol pretreatment increased the choice for cocaine over an alternative monetary reinforcer [35], indirectly indicating higher perceived reward in the combined-use condition. Furthermore, the cocaine “high” during cocaine-alone administration peaked at 15-min administration and had subsided by 180 min, whereas during combined alcohol and cocaine administration it peaked at 30 min and was still reported at 360 min (the end of the test session) [38]. No studies addressing this issue have been published since 2011.

CE Effects Compared to the Effects of Cocaine

The euphoric effects of CE compared to cocaine have been assessed in four controlled human experimental studies (cf. Table 2). Overall, either similar or less pronounced euphoric effects were reported by healthy individuals for equivalent doses of CE compared to cocaine (Table 2). Interestingly, a small qualitative study indicated that CE was experienced as more pleasurable than cocaine due to it being less “edgy” [42]. No studies addressing the relative euphoric effects of CE and cocaine have been published since 2000.

Table 2.

Comparison of the euphoric effects of CE and cocaine (COC) in controlled human studies

Study design	Cocaine dose	CE dose	Results	Reference
Single-blind, placebo-controlled, dose-escalating study in 3 individuals	0.25 mg/kg i.v.	0.25 mg/kg i.v.	CE dose-dependently induced pleasurable subjective effects. Compared with COC, CE produced less intense feelings of arousal and energy, and being less “edgy.” Because of this latter effect, COC was judged as being less pleasurable than CE	Perez-Reyes [42]
Single-blind, crossover study in 6 individuals	0.25 mg/kg i.v.	0.25 mg/kg i.v.	CE resulted in 43% lower ratings of “high” than COC	Perez-Reyes [34]
RCT in 8 individuals	0.92 mg/kg intranasal	0.95 mg/kg intranasal	CE showed similar euphoria to COC	McCance et al. [43]
Double-blind RCT on four test days in 8 individuals	1 mg/kg intranasal	0.5 and 1 mg/kg intranasal, placebo	CE’s “high” was greater than that for the equivalent dose of cocaine, though the difference was not statistically significant	McCance [44]
RCT in 6 individuals	0.25 or 0.5 mg/kg i.v.	0.25 or 0.5 mg/kg i.v.	COC 0.5 mg/kg produced significantly higher ratings of “cocaine high” (p < 0.01), “rush” (p < 0.01), and “good drug effects” (p < 0.01) than CE 0.5 mg/kg	Hart et al. [22]

Effect of Prior Alcohol Use on Cocaine Pharmacokinetics

Cocaine is metabolized by cytochrome P450, butyrylcholinesterase, liver carboxylesterase-1, and carboxylesterase-2 [45, 46]. Using mouse and human liver homogenates, alcohol has been shown to inhibit carboxylesterase-1 and carboxylesterase-2 [46]. As a consequence, simultaneous oral use of alcohol and cocaine in experienced cocaine users resulted in higher cocaine plasma levels, C_max, and AUC (cf. Table 3).

Table 3.

Effect of alcohol pretreatment on the bioavailability of cocaine

Study design	Dose of alcohol	Dose of cocaine	Effect of alcohol pretreatment	Reference
Double-blind crossover RCT in 9 healthy individuals	0.85 g/kg p.o	1.25 and 1.9 mg/kg intranasal	For 1.9 mg/kg: 31% higher Cmax (F(1, 10) = 6.72, p = 0.03), 28% greater AUC0-120 (F(1, 10) = 6.37, p = 0.03), and 39% higher bioavailability (F(1, 10) = 5.14, p = 0.05)	Perez-Reyes and Jeffcoat [36]
Double-blind crossover RCT in 9 healthy individuals	1 g/kg p.o	100 mg intranasal	52% increase in Cmax (p = 0.008) and 40% increase in AUC0–480 (p = 0.008)	Farré et al. [33]
Double-blind RCT in 6 healthy individuals	1 g/kg p.o	2 mg/kg intranasal	Significantly 18–20% higher Cmax and significantly 23–29% higher AUC0–360	McCance-Katz et al. [38]
Double-blind RCT in 8 healthy individuals	100 mg/dL p.o	Four doses of 1 mg/kg intranasal, every 30 min	Cmax 18% higher (p = 0.035) and 15% bigger AUC0–480 min (p = 0.035)	McCance-Katz et al. [39]
Double-blind RCT in 17 subjects who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse	1 g/kg p.o. at 0 min and 0.12 g/kg p.o. at 60 min	1 mg/kg intranasal dosed at 0, 30, 60, and 90 min	AUC was 22% higher, Cmax was 8% higher (both not significant)	McCance-Katz et al. [40]
Double-blind crossover RCT in 10 healthy individuals	1 g/kg p.o	0.3, 0.6, and 1.2 mg/kg (i.v. for 15 min)	No effect on Cmax and AUC, but for alcohol in combination with 1.2 mg/kg cocaine i.v.	Harris et al. [21]

Compared to the cocaine-alone condition, peak plasma levels of cocaine were higher in the cocaine-alcohol condition (366 ± 37 ng/mL and 309 ± 36 ng/mL, respectively), as well as, cocaine AUC (66,544 ± 7,554 vs. 53,992 ± 4,516 ng-min/mL; F = 15.58, df = 2.69, 50, p < 0.001) [38]. Compared to intranasal cocaine alone, its simultaneous use with alcohol (1 g/kg) led to significantly higher cocaine peak plasma levels (18–20%) and AUC_0–360 (23–29%) [38]. In two later studies, cocaine AUC was 22% [40] and 15% [39] greater following cocaine-alcohol administration. When cocaine (100 mg intranasal) was administered simultaneously with alcohol (1 g/kg) to nine experienced healthy individuals, cocaine peak plasma levels increased (C_max: 225.9 vs. 343.8 ng/mL; p = 0.008), as did AUC_0-480 (38,353 vs. 54,037 ng-min/mL; p = 0.008) [33]. Similarly, ingestion of alcohol (0.85 g/kg) 15 min prior to cocaine (1.9 mg/kg intranasal) resulted in significant increases in cocaine peak plasma level (+31%), AUC_{0–120 min} (+28%), and bioavailability (+39%) [36]. Finally, the enhancing effect of alcohol on cocaine plasma levels depends on the timing and order of consumption of the two substances [23, 47]. When cocaine was administered intravenously or smoked after alcohol consumption (thus bypassing hepatic first-pass metabolism), alcohol did not affect AUC or C_max of cocaine [21]. In summary, this series of relatively older studies shows that the pharmacokinetic interaction between alcohol and cocaine, when coadministered orally, increases cocaine peak plasma levels by 18–52% and AUC by 15–40%, compared with cocaine alone.

Impact of CE

Rate of CE Formation

CE is a bioactive metabolite of cocaine which is only formed in the liver only when alcohol and cocaine are used within approximately 2 h of each other. However, the proportion of cocaine converted to CE depends on the route administration: approximately 34% (oral), 17–24% (i.v.), 18% (smoking) [21, 37], and 17% (intravenous) [21]. However, only very small amounts of CE are produced at low cocaine plasma levels, regardless of the amount of alcohol consumed [23]. For instance, when cocaine (100 mg intranasal) was administered simultaneously with alcohol (1 g/kg), CE was detected in plasma (C_max: 53.3 ng/mL; AUC_{0–480 min} 13,331.8 ng-min/mL) [33]. Based on AUC_{0–480 min} of cocaine and CE, approximately 25% of cocaine was converted to CE [33]. Following ingestion of alcohol and intranasal cocaine administration (2 mg/kg), 29% of cocaine was metabolized to CE [38]. In a subsequent study on the COC, 22% of cocaine was converted in CE [39]. In the study of Perez-Reyes [36], CE AUC_{0–120 min} was 12% of that of its parent compound following oral administration of 1.9 mg/kg cocaine. In summary, approximately 12–34% of cocaine used within 2 h after alcohol consumption is metabolized into CE, a psychoactive metabolite of cocaine.

Prolonged Effect of CE

The potency of CE in inducing euphoric effect is similar or lower than that of cocaine (cf. section CE Effects Compared to the Effects of Cocaine). However, with an elimination half-life of 118 to 144 min [21, 40, 43], the duration of action of CE is 2 to 5 times longer. This suggests that the effects of CE are likely equal or somewhat less intense but more prolonged compared to those of cocaine.

Selectivity for the Biogenic Amine Transporters

In an attempt to explain the possible differences in the effects of cocaine and CE, the results of studies on their inhibition of monoamine transporters in vitro were reviewed to provide complementary mechanistic evidence for the risks of COC. The inhibition of the DAT by cocaine is closely related to its reinforcing and addictive properties [48, 49]. Therefore, it is of interest to assess the selective inhibition of dopamine (DA) and serotonin reuptake by cocaine and CE. In addition to inhibiting DAT, cocaine also potently inhibits the SET (5-HT) and NET, both in vitro and in vivo, at concentrations relevant to human use [50, 51]. Table 4 presents data on the interaction of cocaine and CE with the monoamine transporters DAT, SERT, and NET. Cocaine and CE have similar affinity for DAT; however, CE has substantially lower affinity for SERT and NET compared to cocaine. Specifically, CE is approximately 40 times and 50 times less potent as inhibitor of serotonin and noradrenaline reuptake, respectively [20]. Nevertheless, compared with cocaine, CE exhibits 3.4- to 7.8-fold greater selectivity for DAT over SERT [20, 52, 53].

Table 4.

Interaction of cocaine and CE with monoamine transporters for DAT, SERT, and NET

Transporter	Cocaine	CE	Ratio (CE/cocaine)	Reference
​	Ki-value (µM)		​	​
DAT	0.6	0.6	1.0	Hearn et al. [20]
DAT	0.54	–	–	Reith and Selmeci [54]; Ritz et al. [48]
DAT	0.64	–	–	Ritz et al. [55]
DAT	0.2	0.19	0.95	Elsworth et al. [53]
DAT (IC50)	0.3	0.3	1.0	Jatlow et al. [56]
DAT (IC50)	0.1	0.84	8.4	Meiergerd and Schenk [57]
DAT (IC50)	0.39	0.36	1.0	Bradberry et al. [52]
SERT	0.2	7.9	40.0	Hearn et al. [20]
SERT	0.14	–	​	Reith et al. [48]; Ritz et al. [55]; Ritz et al. [48]
SERT	0.2	0.64	3.2	Elsworth et al. [53]
SERT (IC50)	0.23	1.7	7.4	Bradberry et al. [52]
NET	–	33.0	–	Hearn et al. [20]
NET	1.6	–	–	Reith and Selmeci [54]; Ritz et al. [55]; Ritz et al. [58]; Ritz et al. [48]
​	DAT/SERT selectivity			​
​	3.0 (0.6/0.2)	13.2 (7.9/0.6)	4.4	Hearn et al. [20]
​	3.9 (0.54/0.14)	–	–	Ritz et al. [48]
​	4.6 (0.64/0.14)	–	–	Ritz et al. [55]
​	1.0 (0.2/0.2)	3.4 (0.64/0.19)	3.4	Elsworth et al. [53]
​	0.60 (0.23/0.39)	4.7 (1.7/0.36)	7.8	Bradberry et al. [52]

In summary, due to the absence of strong serotonergic inhibition, CE demonstrates greater selectivity for dopaminergic activity than cocaine. This may partly explain the enhanced euphoria reported by individuals who co-use alcohol and cocaine, compared to those who use cocaine alone and therefore do not produce CE as a psychoactive metabolite.

Discussion

Anecdotal data and qualitative studies have reported that COC induces more intense and prolonged feelings of euphoria compared to cocaine alone. This first integrative review synthesizes quantitative controlled human studies, confirming the findings of qualitative studies and elucidating the mechanisms underpinning the more intensive and longer lasting euphoria observed following COC. Although most of the included studies were published decades ago, this is the first integrative review of quantitative studies addressing at all relevant aspects of the interaction between alcohol and cocaine.

The data depicted in Table 1 consistently show that COC induces significantly stronger and more prolonged ratings of cocaine “high” compared to cocaine alone. This may be explained as follows. First, alcohol ingested prior to cocaine inhibits cocaine metabolism, leading to higher bioavailability and increased peak plasma levels of cocaine [33, 36, 38, 39]. In addition, alcohol-induced nasal capillary vasodilation may contribute to more rapid cocaine absorption and increased nasal bioavailability [21]. Second, when alcohol and cocaine are co-used, the unique metabolite CE is formed, which retains biological activity, including the induction of euphoria. The metabolic conversion of orally administered cocaine to CE ranges from 12% to 34% [23, 33, 36, 38, 39], but the conversion rate is lower after intravenous administration [21] or smoking [21, 37]. Once formed, CE induces similar or somewhat lower levels of euphoria compared to cocaine [59] (cf. Table 2). However, CE has a longer plasma elimination half-life; thus, its pleasurable and euphoric effect may last longer than those of cocaine. Finally, based on inhibition of monoamine transporters (cf. Table 4) CE seems to exhibit greater selectivity for dopaminergic activity than cocaine, which may further contribute to the enhanced euphoria reported by individuals who co-use alcohol and cocaine, compared to those who use cocaine alone.

The dopaminergic system is generally considered to be involved in the reinforcing properties of cocaine, and, to some extent, in its euphoric effects [48, 60, 61], whereas the role of serotonin (5-HT) in the addictive potential of cocaine remains less clear. This issue was further elaborated using the results of studies on their inhibition of monoamine transporters in vitro and the outcome served as complementary mechanistic evidence.

Stimulants, like cocaine, bind at the DAT and inhibit DA reuptake in the synaptic cleft which leads to significant potentiation of dopaminergic transmission in mesolimbo-cortical pathways ultimately causing reinforcement. A growing body of evidence supports the hypothesis that abuse potential of drugs is determined by their relative selectivity to act at DAT vs. SERT [62–64]. With respect to their inhibitory actions on DAT, cocaine and CE show equivalent affinity (cf. Table 4). This is consistent with preclinical studies demonstrating equipotency of cocaine and CE in dopaminergic assays. For instance, equipotency was observed in inhibition of the binding of the specific DA uptake blocker [³H]GBR 12935 to rat striatal membranes, as well as the uptake of DA into striatal synaptosomes [53, 56, 65]. Using microdialysis in anesthetized rats, intravenously administered CE and cocaine showed also equipotency in their ability to increase extracellular DA concentrations in the nucleus accumbens [56, 66]. In contrast to their equipotency at DAT, CE is 3.2 to 40 times less potent as an inhibitor of SERT [20], resulting in a 3.4- to 7.8-fold higher selectivity for DAT over SERT compared to cocaine [20, 52, 53]. This higher DAT selectivity of CE is supported by microdialysis data [52], in which cocaine and CE (both at 4 µmol/kg, i.v.) increased extracellular DA levels in the nucleus accumbens to approximately 400% of baseline. However, whereas CE had no effect on striatal serotonin levels, cocaine significantly increased serotonin to 200% of baseline [52]. The substantially lower potency of CE at SERT has important implications, as SERT activity is thought to temper dopaminergic reinforcement. This aligns with findings by Roberts et al. [64] who demonstrated that in a series of cocaine analogues, the DAT/SERT selectivity ratio correlated more strongly with reinforcing potency (self-administration behavior) than did DAT binding affinity alone. Lacking this serotonergic “brake”, CE may represent a purer rewarding substance than cocaine [67], which may also explain why CE has been reported as more pleasurable than cocaine due to its less “edgy” subjective effect [42].

In summary, alcohol enhances the euphoric effects of cocaine by altering its metabolism and promoting the formation of CE, a metabolite that prolongs and amplifies the sympathomimetic effects of cocaine, producing a more intense high. In addition, due to the higher DAT/SERT selectivity of CE, COC may have a greater reinforcing potency (and therefore higher dependence potential) than cocaine alone. Although a variety of motives have been reported for the COC, we suggest that the enhanced and prolonged “high” represents a key driver of simultaneous use. As Steven B. Karch noted, “Cocaethylene explains why so many cocaine users use alcohol. They’re getting a higher “high” and a longer “high”. More bang for their buck” [67]. Consequently, the combination is more likely to be abused than cocaine alone.

The high popularity of this combination, however, carries significant health risks. Individuals who co-use cocaine and alcohol generally exhibit poorer overall health, experience worse outcomes in treatment programs [68, 69], and are at higher risk of emergency department admission [7, 70], primarily due to cardiovascular complications [3]. CE may play a prominent role in these adverse outcomes [29, 71], as it has been associated with a 40-fold increase in the risk of acute cardiac incidents and an 18- to 25-fold higher risk of sudden death compared to cocaine alone [59, 72]. COC has also been linked to increased overall mortality compared with the use of cocaine alone [3]. With its longer half-life, CE remains active in the body for up to 7 h after the last traces of cocaine have been eliminated, prolonging and intensifying the subjective “high”. COC also results in greater self-reported consumption of both substances than when used separately [10], potentially increasing vulnerability to developing cocaine use disorder and alcohol use disorder. Finally, clinical evidence indicates that alcohol consumption can precipitate relapse among cocaine abusers during abstinence [73], likely contributing to lower retention rates in treatment programs [74]. We therefore advocate that individuals should be informed about the substantial health risks associated with simultaneous use of alcohol and cocaine.

Limitations

A limitation of this review is that the literature included is relatively old, though this does not necessarily imply low quality. Furthermore, many studies were performed in small and heterogeneous samples, and occasionally dosing and routes of administration, the timing of alcohol and cocaine use and outcome measures are not fully specified.

Using the six items of the SANRA scale, the Scale for the Assessment of Narrative Review Articles [75], a sum score across all manuscripts of 10.5 points was obtained. Therefore, the current review complies with the criteria of narrative review.

The results depicted in Tables 1 and 2 indicate that the COC induces higher ratings of euphoria/“high” compared to the use of cocaine alone. However, the rating of euphoria in the qualitative studies was not fully consistent with the ratings in the quantitative studies since many of the recreational users who were interviewed did not mention scientifically accepted term like “euphoria or “high” – “but rather qualifications like “well-being”, “good effects,” and “feeling good” to rate the primary subjective sensation of cocaine. These less appropriate qualifications were regarded here as overlapping (less strong) proxies of euphoria.

The results obtained in in vitro studies on monoaminergic transporters depicted in Table 4 were presented as complementary mechanistic evidence for the more prominent dopaminergic profile of CE compared to cocaine. However, the use of DAT:SERT selectivity as proxy of dependence liability of cocaine and CE [62, 63] may be a simplification as other factors may also contribute to their pharmacological actions. This may limit the evidence base of CE being a purer rewarding substance than cocaine.

Statement of Ethics

A statement of ethics is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Van Amsterdam conceptualized and framed the paper, led the manuscript, and wrote the first draft with contributions from van den Brink. Van den Brink also provided critical feedback, contributed to editing and revision of the manuscript, and acted as supervisor. The final version of the manuscript has been reviewed and approved by van Amsterdam and van den Brink.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

This study is based exclusively on published literature which is included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.