ORIGINAL RESEARCH published: 27 February 2019 doi: 10.3389/fphar.2019.00131 Soy Isoflavone Extract Does Not Increase the Intoxicating Effects of Acute Alcohol Ingestion in Human Volunteers Roser Martínez-Riera 1,2,3† , Clara Pérez-Mañá 2,4† , Esther Papaseit 2,4† , Francina Fonseca 1,2 , Rafael de la Torre 5,6 , Nieves Pizarro 2,5 , Marta Torrens 1,2* and Magí Farré 2,4 1 Institut de Neuropsiquiatria i Addiccions, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain, 2 Department of Psychiatry and Legal Medicine and Department of Pharmacology, Therapeutics and Toxicoloy, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain, 3 Red de Salud Mental Gipuzkoa, Osakidetza, San Sebastián-Donostia, Spain, 4 Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (IGTP), Badalona, Spain, 5 Integrative Pharmacology and Systems Neurosciences Research Group, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain, 6 Department of Experimental and Health Sciences (CEXS), Universitat Pompeu Fabra, Barcelona, Spain Soy beans contain isoflavones, including daidzein and genistein, with biological activities related to therapeutic effects in reducing osteoporosis, decreasing adverse Edited by: menopausal manifestations, providing protection from cardiovascular diseases, and Juan J. Canales, reducing hormone-dependent cancers and age-related cognitive-decline. Daidzein has University of Tasmania, Australia been described as inhibiting the aldehyde-dehydrogenase-2 enzyme (ALDH2), and Reviewed by: Edward John Ogden, reducing alcohol use in clinical pilot studies. Our aim was to evaluate the possible Swinburne University of Technology, interactions between a soy extract product and alcohol in a crossover, single blind, Australia randomized study. Ten healthy male volunteers participated in two experimental Paluri Sai Shantanu Rao, University of Findlay, United States sessions: one with a single dose of alcohol (0.5 g/kg, Vodka Absolut, Sweden), and the *Correspondence: other with four capsules of a soy extract product (Super-Absorbable Soy Isoflavones, Marta Torrens Life-Extension, United States) and, 2 h later, the same dose of alcohol. Results Mtorrens@parcdesalutmar.cat † These showed no differences in vital signs except a slightly higher significative reduction in authors have contributed equally to this work and share diastolic blood pressure at 2, 3, 4, and 8 h after administration with alcohol alone in first authorship comparison with soy extract+alcohol. Ethanol-induced subjective and adverse effects were similar for both conditions with the exception of headache (higher at 8 h after Specialty section: This article was submitted to alcohol alone). Our results demonstrate that a single dose of a soy isoflavone extract did Neuropharmacology, not influence alcohol pharmacokinetics and pharmacological effects and did not induce a section of the journal Frontiers in Pharmacology any disulfiram-reaction symptoms. Soy extract and alcohol did not interact and can be Received: 16 October 2018 administered safely. Accepted: 05 February 2019 Keywords: soy extracts, isoflavones, daidzein, genistein, aldehyde-dehydrogenase-2 enzyme, alcohol, Published: 27 February 2019 clinical trial Citation: Martínez-Riera R, Pérez-Mañá C, Papaseit E, Fonseca F, de la Torre R, Pizarro N, Torrens M and Farré M INTRODUCTION (2019) Soy Isoflavone Extract Does Not Increase the Intoxicating Effects Isoflavones are biologically active polyphenols found in soybeans and other legumes. In the of Acute Alcohol Ingestion in Human former, the principal ones are daidzin (40%) and genistin (50%) which transform into two active Volunteers. Front. Pharmacol. 10:131. compounds, daidzein and genistein, respectively (U.S. Department of Agriculture, Agricultural doi: 10.3389/fphar.2019.00131 Research Service, 2015). Daidzein is also metabolized by intestinal bacteria to the active Frontiers in Pharmacology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication compound equol. Daidzein consumption has been related MATERIALS AND METHODS to phytoestrogen and antioxidant activity, a lower incidence of menopausal symptoms (Messina, 2014), and a reduction Study Design in osteoporosis, breast cancer, and cardiovascular diseases The study protocol was approved by the local Human Research (Michelfelder, 2009). This isoflavone is more selective for Ethics Committee (CEIC-Parc de Salut Mar) and conducted in estrogen receptor (ER)/beta than estradiol which could accordance with the Helsinki Declaration and local legislation. explain such activities. The ingestion of soy isoflavones The trial was registered in a public database (ClinicalTrials.gov is considered safe, the most common adverse effects are Identifier: NCT02309801). All the participants were informed gastrointestinal (diarrhea) and more rarely headache, about the study and signed a written informed consent prolonged menstrual period, amenorrhea, dizziness, and before participation. All subjects were financially compensated musculoskeletal complaints (Michelfelder, 2009). Some for their participation. isoflavones, especially daidzin-daidzein, have been reported The study was a randomized, single-blinded (the participants to inhibit the aldehyde-dehydrogenase-2 enzyme (ALDH2) (Gao were informed that they could receive different doses of alcohol et al., 2001; Lowe et al., 2008; Koppaka et al., 2012). in the two sessions), and crossover clinical trial. Subjects Kudzu (Pueraria lobata) root extracts and flowers contain participated in two different experimental sessions separated by isoflavones, for instance, puerarin (about 60% of the total at least 3 days. In one session they received a glass of water isoflavones), and daidzin. Kudzu is used in traditional (240 mL) and 2 h later a single oral dose of alcohol was Japanese and Chinese medicine to treat alcohol hangover administered (0.5 g/kg, Vodka Absolut 40◦ , Sweden); in the R and alcohol substance use disorder (Overstreet et al., 2003a,b). other, they were given four capsules containing a soy extract Some studies in animal models have shown that daidzin product with a glass of water (240 mL) and 2 h later the and synthetic analogs have the capacity to reduce alcohol same dose of alcohol. intake (Overstreet et al., 1996; Gao et al., 2003; Arolfo et al., 2009). In humans, a pilot study in a naturalistic Soy Isoflavone Extract setting demonstrated that the administration of a kudzu A commercial soy extract product (Super-Absorbable extract reduced alcohol consumption in heavy drinkers Soy Isoflavones , hard gelatin capsules, Life-Extension, R (Lukas et al., 2005). In controlled clinical trials with healthy United States) was employed. According to the manufacturer volunteers, a reduction in alcohol intake when kudzu each capsule contained 54 mg of total isoflavones (22 mg extract isoflavones were taken before drinking was reported daidzin-daidzein, 28 mg genistin-genistein, and 4 mg (Penetar et al., 2012; Lukas et al., 2013; Penetar et al., 2015). glycitin-glycitein). The dose administered (four capsules) was As already established, alcohol is biotransformed chosen in order to provide a total content of daidzin/daidzein enzymatically to acetaldehyde by alcohol-dehydrogenase (ADH) (approximately 88 mg) which represented twice the dose and later metabolized into acetate by aldehyde-dehydrogenase recommended for the symptomatic therapy of menopausal (ALDH1). Disulfiram, used for the treatment of alcohol symptoms (Brewer, 1984; Christensen et al., 1991; Gao et al., substance use, inhibits ALDH1 and ALDH2 irreversibly, 2001) or that used in trials for asthma therapy (Smith et al., 2015). producing an accumulation of acetaldehyde concentrations in blood which leads to undesirable effects if alcohol is simultaneously consumed. Symptoms, which include Subjects sickness, nausea, vomit, sweating, dizziness, and facial A total of 10 healthy males were recruited from a volunteer erythema, are known as the “disulfiram-reaction” database. The screening visit took place within the 3 weeks prior or “antabuse-reaction.” to commencing the study sessions. Subjects underwent a general For centuries traditional Chinese medicine has employed physical examination, a 12-lead ECG, and a complete blood different isoflavones for the treatment of alcohol substance use and urine analysis, including drugs of abuse in urine. Inclusion (Keung, 2003; Lu et al., 2009; Soyka and Rösner, 2010) with criteria were (i) recreational use of alcohol (<4 units of alcohol the advantage that they do not affect acetaldehyde levels, induce per day); (ii) previous experience of acute alcohol intoxication; disulfiram-like effects (Penetar et al., 2011), or alter the sleep cycle and (iii) no history of substance abuse/dependence according (Bracken et al., 2011). to the Diagnosis and Statistical Criteria for Mental Disorders There are no previously published papers evaluating the (DSM-IV-R). Exclusion criteria were (i) current tobacco smokers; possible interference/influence of soy isoflavone extracts on (ii) current or previous history of mental disorders; (iii) any alcohol pharmacokinetics, acute pharmacological effects, and somatic illness that could interfere with alcohol and soy; (iv) induction of a “disulfiram-like effect” despite their potential the consumption of >5/day drinks of tea, coffee or similar interaction in the treatment of alcohol abuse. The aim of xanthine-containing beverages during the 3 months prior to the present study was to evaluate the interactions between the study; and (v) the use of soy derivatives during the a soy extract containing isoflavones and alcohol, in relation previous month. to the pharmacokinetics and acute effects of alcohol, in order to design future clinical trials to assess the possible Procedure therapeutic effects of isoflavones on substance use disorders, Subjects were admitted to the Clinical Research Unit facilities specifically cocaine. at 07:45 a.m. after an overnight fast. Upon arrival, they Frontiers in Pharmacology | www.frontiersin.org 2 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication were asked about any drug consumption or adverse event An intravenous catheter in the non-dominant arm was inserted that could affect their participation. They were requested to for blood sampling. refrain from using any psychoactive drug for a minimum of 7 days prior to the study and throughout it, and Physiological and Subjective Effects from consuming caffeinated products for 24 h and alcohol Non-invasive systolic blood pressure (SBP), diastolic blood for 48 h. They were also asked to follow a diet free pressure (DBP), heart rate (HR), oral and cutaneous from daidzein (soy and derivatives) 3 days before and facial temperature (OT, FT) were repeatedly recorded at 48 h after each session. A urine sample was collected baseline, immediately before capsule administration, and at 2 for drug of abuse testing (Instant-View , Multipanel 10 R (immediately before beverage administration), 2.5, 3, 4, 5, 6, 8, Test Drug Screen, Alfa Scientific Designs Inc., Poway, CA, and 10 h after first administration. All assessments were carried United States). Alcohol concentrations in breath were analyzed. out with a DinamapTM 8100-T vital signs monitor (Critikon, TABLE 1 | Summary of results of the physiological and subjective effects observed after administration of soy extract+alcohol and alcohol (n = 10). Variable Parameter Soy extract+Alcohol Alcohol P-value Physiological SBP Emax −4.5 ± 11.66 −9.2 ± 11.05 0.323 AUC0−10 −24.4 ± 40.4 −39.17 ± 41.7 0.302 DBP Emax −4.8 ± 9.92 −10.5 ± 8.72 0.081 AUC0−10 −25.8 ± 41.36 −58.8 ± 35.59 0.052 HR Emax −3.7 ± 13.09 −1.2 ± 15.26 0.368 AUC0−10 −14.9 ± 61.2 −9.75 ± 59.58 0.759 OT Emax −0.26 ± 0.31 −0.23 ± 0.47 0.873 AUC0−10 −0.967 ± 1.159 −1.2 ± 2.19 0.747 FT Emax 0.75 ± 1.34 1.59 ± 0.67 0.039 AUC0−10 6.04 ± 7.2 8.1 ± 5.59 0.205 Visual Analog Scales Drunkenness Emax 17.6 ± 29.018 20.8 ± 19.1 0.602 AUC0−10 35.36 ± 84.037 25.387 ± 35.1 0.569 Content Emax 18.1 ± 30.2 23.9 ± 26.2 0.361 AUC0−10 29.687 ± 67.9 29.91 ± 47.07 0.980 Nausea Emax 0.5 ± 1.58 0.8 ± 1.75 0.718 AUC0−10 0.2 ± 0.79 1.1 ± 3.1 0.416 Vertigo Emax 3.2 ± 10.119 2.2 ± 6.9 0.812 AUC0−10 5.27 ± 16.68 0.9 ± 3 0.449 Dizziness Emax 9.4 ± 22.667 10.9 ± 18.3 0.687 AUC0−10 19.9 ± 55.3 22.7 ± 47.09 0.627 Face flushing Emax 7.5 ± 13.938 9.6 ± 14.9 0.696 AUC0−10 16.3 ± 37.38 10.98 ± 20.8 0.614 Headache Emax 5.3 ± 9.58 16.2 ± 27.9 0.217 AUC0−10 18.16 ± 40.4 48.3 ± 87.9 0.274 Breathing difficulty Emax 0 0 − AUC0−10 0 0 − ARCI questionnaire ARCI-PCAG Emax 2.4 ± 3.6 3.4 ± 3.59 0.266 AUC0−10 9.8 ± 14.56 14.05 ± 14.2 0.237 ARCI-MBG Emax 2.6 ± 2.836 2.7 ± 3.3 0.876 AUC0−10 4.48 ± 5.01 3.4 ± 3.2 0.329 ARCI-LSD Emax 4.8 ± 1.47 5.2 ± 1.7 0.373 AUC0−10 42.26 ± 7.1 43.2 ± 8.27 0.328 ARCI-LSD Emax 4.5 ± 0.97 4.6 ± 1.07 0.882 AUC0−10 38.26 ± 5.8 36.7 ± 5.5 0.355 ARCI-BG ARCI-A Emax 1.4 ± 1.4 1.8 ± 1.686 0.168 AUC0−10 3.07 ± 3.8 4.5 ± 4.47 0.113 Values are differences from baseline (mean values and standard deviation). Systolic blood pressure (SBP, mmHg); diastolic blood pressure (DBP, mmHg), heart rate (HR, beats/min), (temperature (T, ◦ C), visual analog scale (VAS, mm), Addiction Research Center Inventory questionnaire (ARCI, score), Emax = maximal/peak effects, AUC0−10 , area under the curve from 0 to 10 h. Frontiers in Pharmacology | www.frontiersin.org 3 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication Tampa, FL, United States). Cutaneous facial temperature was 24 h after soy extract administration. Ethanol was determined measured at the same time with an additional monitor (Critikon, in blood (DRI Ethyl Alcohol Assay, Thermo Fisher, Fremont, R Tampa, FL, United States). CA, United States) and breath (Alcotest, Dräger, Germany). Subjective effects were evaluated using a set of visual analog Daidzein, genistein, and the endogenous metabolite equol scales (VAS) at baseline (0 h), 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 5, 6, 8, were determined by liquid chromatography coupled to tandem and 10 h after first administration. VAS (100 mm) were labeled mass spectrometry (LC/MS/MS) using a validated method with different adjectives marked at opposite ends from “not at all” (Rodríguez-Morató et al., 2015). to “extremely” (Peiró et al., 2013; Farré et al., 2015; Papaseit et al., 2016). Subjects were asked to rate effects of drunkenness, content, Statistical Analysis nausea, vertigo, dizziness, feeling of face flushing, headache, and Effects breathing difficulty. Differences with respect to baseline were calculated for vital signs In addition, the 49-item short form Addiction Research (SBP, DBP, HR, and OT-FT) and subjective effects (VAS, ARCI). Center Inventory (ARCI) was administered at baseline and at Maximum/peak effects (Emax) and the time to reach maximum 2, 2.75, 3.5, and 10 h after first treatment administration. The effects (tmax) were also determined for the previously mentioned Spanish validated version of the ARCI (Lamas et al., 1994) is variables. The area under the curve of the concentrations from 0 sensitive to the effects of a variety of drug of abuse classes with five to 10 h (AUC0−10 h ) using the trapezoidal rule was calculated for subscales: PCAG (pentobarbital-chlorpromazine-alcohol group, vital signs and subjective effects. a measure of sedation); MBG (morphine-benzedrine group, a For the statistical comparison of AUC and Emax a measure of euphoria); LSD (lysergic acid diethylamide group, a Student’s t-test for paired samples was employed. For tmax a measure of dysphoria and somatic symptoms); BG (benzedrine non-parametric Wilcoxon test was used. A repeated measure group, a stimulant subscale relating to intellectual efficiency and ANOVA with two factors (treatment and time) was used to energy); and A (amphetamine, a measure of d-amphetamine compare the time course of effects. When treatment or the effects) (Farré et al., 2015). treatment × time interaction was statistically significant, multiple Tukey post hoc comparisons were performed at each time point. Pharmacokinetics Blood samples and ethanol breath concentrations were collected Experimental Pharmacokinetic Parameters at baseline (before soy extract administration), and at 2 (before Peak concentration (Cmax), time to reach peak concentrations ethanol administration), 2.25, 2.5, 2.75, 3, 4, 5, 6, 7, 8, 10, and (Tmax), and area under the concentration-time curve from 0 to FIGURE 1 | Time course of the physiological and subjective effects after administration of alcohol and soy extract+alcohol. Mean values and standard error (n = 10). Figures correspond to systolic and diastolic blood pressure (mmHg), heart rate (beats/min), and drunkenness (mm). Frontiers in Pharmacology | www.frontiersin.org 4 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication FIGURE 3 | Plasma concentrations of daidzein and genistein after the administration of the soy extract. Mean values and standard error (n = 10). FIGURE 2 | Plasma concentrations of ethanol after the administration of alcohol and soy extract + alcohol. Mean values and standard error (n = 10). DBP HR). A slight difference in cutaneous facial temperature TABLE 2 | Pharmacokinetic parameters of alcohol in plasma (n = 10). was found in the Emax (1.59 and 0.75◦ C after alcohol and soy extract+alcohol, respectively). In the time course analysis, a Pharmacokinetic Soy extract + Alcohol Alcohol P-value slightly higher reduction of DBP was reported at 2 h (−2.89, 0.8; parameters p < 0.05), 3 h (−4.5, −0.3; p < 0.05), 4 h (−9.67, −3.3; p < 0.01), Mean ± SD Mean ± SD and 8 h (−4.78, −1; p < 0.05) after administration with alcohol Cmax (ng/ml) 77 ± 16.99 77 ± 22.25 1 alone in comparison with soy extract+alcohol, respectively. AUC0−10 (ng/ml/h) 216.57 ± 30.40 219.67 ± 27.2 0.806 Tmax (h)∗ 2.75 (2.5-4) 3 (2.5-4) 0.256 Subjective Effects Mean values and standard deviation) (mean values and standard deviation) for In VAS, alcohol and soy extract+alcohol showed very similar Cmax and AUC. Median values and range for Tmax. AUC, area under the curve; subjective effects (drunkenness, content, nausea, vertigo, Cmax, peak/maximal concentration; SD, standard deviation; Tmax, time to reach dizziness, face flushing, and breathing difficulty), without peak concentrations. ∗ Median values and range for Tmax (Wilcoxon test). statistically significant differences (Figure 1, drunkenness). However, the alcohol alone condition, in contrast to the soy 10 h (AUC0−10 ) from ethanol plasma concentrations over time extract+alcohol, showed higher scores for headache at 8 h were determined using Pharmacokinetic Functions for Microsoft (16 mm, 3.7 mm, respectively, p < 0.01). Excel (Joel Usansky, Atul Desai, and Diane Tang-Liu, Department With regard to the ARCI questionnaire, no differences were of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA, reported between alcohol and soy extract+alcohol. United States). All statistical tests were performed with the PASW Statistics Alcohol Concentrations 18.0 (SPSS, Chicago, IL, United States). A value of p < 0.05 was Pharmacokinetic parameters for blood ethanol concentrations considered statistically significant. over time curves are shown in Figure 2. No differences were observed for ethanol concentrations in blood between alcohol RESULTS and soy extract+alcohol (Table 2). In both conditions, 10 h after drug administration, alcohol concentrations in plasma were Subject Characteristics deemed undetectable. The 10 healthy male participants had a mean age of 25.2 ± 3.6 years, mean weight 74.0 ± 7.0 kg, and a body mass Daidzein, Genistein, and Equol index of 23.3 ± 2.6. The participants consumed ethanol regularly Concentrations (10.0 ± 7.1 standard drinks/week; 1 standard drink = 10 g of Pharmacokinetic parameters for blood isoflavone concentrations pure ethanol). All subjects completed the study. None required (daidzein and genistein) over time curves are shown in special therapy or care throughout the study and no serious Figure 3. Daidzein-concentrations peaked at 6.1 h (±3.2) after adverse events occurred during the experimental sessions. administration and genistein at 7.3 h (±3). The mean Cmax of daidzein was 1016.5 ng/ml (±303.1) and genistein 1039.0 ng/ml Physiological Effects (±496.9). The concentrations of equol, a metabolite of daidzein, Table 1 shows a summary of the physiological and subjective peaked at 24 h. Its pharmacokinetic parameters could not be effects. Regarding vital signs, no differences were observed in calculated due to a limited number of evaluations (24 h). Multiple Emax and AUC for SBP, DBP, HR, and oral temperature between peaks along the plasma concentrations over time suggest an both conditions: alcohol and soy extract+alcohol (Figure 1, SBP, enterohepatic recirculation of isoflavones. Frontiers in Pharmacology | www.frontiersin.org 5 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication DISCUSSION substance use disorders. Moreover, only males participated as isoflavones could present gender-based differences in metabolism According to our findings, soy isoflavones neither interact with (Soukup et al., 2016). Our research was performed using a alcohol nor induce disulfiram-like effects with respect to alcohol single dose of isoflavones and a standard dose of alcohol pharmacokinetics and effects (vital signs and subjective/adverse for interaction studies. As the selected isoflavone dose was effects). A previous study (Penetar et al., 2011) also suggested within the range of safe menopause symptom therapy, we that the administration of a purified extract of a kudzu are unable to advance results employing higher doses and/or herbal medication containing isoflavones (mostly puerarin repeated administrations. Disulfiram-like symptoms also appear [19%], followed by daidzin [4%], and daidzein [2%]) did not at low-medium doses of alcohol when ALDH1 inhibitors are increase the intoxicating effects of acute alcohol consumption in administered (Kline et al., 1987; Visapää et al., 2002). We human volunteers (blood alcohol levels, subjective effects, and employed a natural extract with a mixture of isoflavones and psychomotor performance). are thus unaware of whether the results could change after a We only found slightly significative changes in headache single dose of each pure isoflavone or metabolite such as equol. and, at some time points, facial temperature, and diastolic Our study did not include a placebo condition, nevertheless, blood pressure when alcohol was administered. Such minimal the non-significant symptomatic differences reported between changes could have been attributed to placebo (nocebo) effects, the groups could be explained by placebo/nocebo effects. nevertheless, as a placebo capsule condition was not included we Neither were acetaldehyde concentrations analyzed nor any cannot substantiate this interpretation. measure of psychomotor performance performed. The fact Our results were similar to a previous pharmacokinetic that Japanese and Chinese food contains elevated doses of study in which the pharmacokinetic parameters for blood isoflavones, and there are no adverse effects when alcohol is isoflavone concentrations showed double peaks in time- consumed, could support our results demonstrating a possible course plasma, thus supporting enterohepatic recirculation, isoflavone mechanism of action on ALDH2. We did not, characteristic of isoflavone metabolism (Rodríguez-Morató et al., however, include a measure of the activity of these enzymes, 2015). We observed that the Tmax for alcohol appeared and our findings do not provide significant evidence about between 2.5 and 4 h after administration, the Tmax for the effect of soy extract on human aldehyde-dehydrogenase the first peak for daidzein-genistein was between 2 and (or ALDH) isozymes. 4 h, and the maximal concentrations of both isoflavones were around 6 h. During 0.5–6 h blood alcohol levels were higher than those recommended for driving, within the CONCLUSION range of the maximal isoflavone concentrations. As isoflavones show intensive presystemic metabolism concentrations in the Substances such as soy isoflavones can be safely administered in liver they could be elevated enough at 0.5–2 h to inhibit combination with alcohol. They could be a new strategy for the hepatic metabolic enzymes (Chandrasekharan and Aglin, 2013; treatment of substance use disorders without involving the risks Rodríguez-Morató et al., 2015). We are, however, unaware of the associated with disulfiram. consequences of alcohol administration regarding the time peak of isoflavone concentrations. In contrast to disulfiram, some isoflavones are strong DATA AVAILABILITY reversible inhibitors of ALDH2 and mild inhibitors of ALDH1. The datasets for this manuscript are not publicly available In the central nervous system, blocking ALDH2 inhibits because Data will be available to other researchers following dopamine metabolism by hindering the conversion of DOPAL publication. Requests to access the datasets should be directed to to DOPAC, increasing levels of aldehyde DOPAL, and forming mtorrens@parcdesalutmar.cat. tetrahydropapaveroline (THP) in the ventral tegmental area. THP inhibits tyrosine hydroxylase (TH) and consequently decreases dopamine biosynthesis thus blunting the reinforcing AUTHOR CONTRIBUTIONS effects of cocaine (Yao et al., 2010). In male mice, daidzein and genistein decreased cocaine-reinforcing effects, and daidzein, but MF, MT, EP, CP-M, FF, and RM-R conceptualized the study not genistein, reduced cue-induced cocaine relapse (Martin et al., design. MF, EP, CP-M, and RM-R collected the data. RdlT and 2013). Alcohol is a substance commonly abused in combination NP analyzed the alcohol and isoflavones. MF, MT, EP, CP-M, FF, with cocaine. A number of studies have found that about RdlT, and RM-R wrote the manuscript. 60% of individuals with cocaine use disorder have co-occurring diagnoses of alcohol use disorder (Araos et al., 2017). Taking into account the pharmacodynamic profile of isoflavones, they could FUNDING be used for future clinical trials studying possible treatments for substance use disorders (alcohol and cocaine,), without requiring This work was supported by the following projects (Instituto absolute alcohol abstinence as an inclusion requirement. de Salud Carlos III-ISCIII Red de Trastornos Adictivos-RTA Our study has some limitations. The sample included a RD16/0017/0003 and RD16/0017/0010, Juan Rodés JR16/00020), small number of healthy volunteers and not patients with integrated in the National R + D + I and funded by the Frontiers in Pharmacology | www.frontiersin.org 6 February 2019 | Volume 10 | Article 131 Martínez-Riera et al. Soy Isoflavone Extract and Alcohol Intoxication ISCIII and the European Regional Development Fund Recerca AGAUR Gencat (2017 SGR 316, 2017 SGR 530, (FEDER). In addition, by grants from Ministerio de and 2017 SGR 138), and Instrumental Action for the Sanidad, Política Social e Igualdad (Plan Nacional Sobre Intensification of Health Professionals-Specialist Practitioners Drogas, PNSD 2015I054 and 2016I024), Suport Grups de (PERIS: SLT006/17/00014). REFERENCES Lukas, S. E., Penetar, D., Berko, J., Vicens, L., Palmer, C., Mallya, G., et al. (2005). An extract of the Chinese herbal root kudzu reduces Araos, P., Vergara-Moragues, E., González-Saiz, F., Pedraz, M., García- alcohol drinking by heavy drinkers in a naturalistic setting. Alcohol. Marchena, N., Romero-Sanchiz, P., et al. (2017). Differences in the Clin. Exp. Res. 29, 756–762. doi: 10.1097/01.ALC.0000163499. rates of drug polyconsumption and psychiatric comorbidity among 64347.92 patients with cocaine use disorders according to the mental health Lukas, S. E., Penetar, D., Su, Z., Geaghan, T., Maywalt, M., Tracy, M., et al. service. J. 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Drugs 15, 695–711. doi: 10.1517/14728214.2010.50 be construed as a potential conflict of interest. 0811 U.S. Department of Agriculture, Agricultural Research Service (2015). USDA Copyright © 2019 Martínez-Riera, Pérez-Mañá, Papaseit, Fonseca, de la Torre, Database for the Isoflavone Content of Selected Foods, Release 2.1. Nutrient Pizarro, Torrens and Farré. This is an open-access article distributed under the Data Laboratory. Available at: http://www.ars.usda.gov/nutrientdata/isoflav terms of the Creative Commons Attribution License (CC BY). The use, distribution [accessed January 4, 2019]. or reproduction in other forums is permitted, provided the original author(s) and Visapää, J. P., Tillonen, J. S., Kaihovaara, P. S., and Salaspuro, M. P. (2002). Lack of the copyright owner(s) are credited and that the original publication in this journal disulfiram-like reaction with metronidazole and ethanol. Ann. Pharmacother. is cited, in accordance with accepted academic practice. No use, distribution or 36, 971–974. reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 8 February 2019 | Volume 10 | Article 131