Anandamide and 2-arachidonoylglycerol baseline plasma concentrations and their clinical correlate in gambling disorder.

INTRODUCTION: Different components of the endocannabinoid (eCB) system such as their most well-known endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), have been implicated in brain reward pathways. While shared neurobiological substrates have been described among addiction-related disorders, information regarding the role of this system in behavioral addictions such as gambling disorder (GD) is scarce. AIMS: Fasting plasma concentrations of AEA and 2-AG were analyzed in individuals with GD at baseline, compared with healthy control subjects (HC). Through structural equation modeling, we evaluated associations between endocannabinoids and GD severity, exploring the potentially mediating role of clinical and neuropsychological variables. METHODS: The sample included 166 adult outpatients with GD (95.8% male, mean age 39 years old) and 41 HC. Peripheral blood samples were collected after overnight fasting to assess AEA and 2-AG concentrations (ng/ml). Clinical (i.e., general psychopathology, emotion regulation, impulsivity, personality) and neuropsychological variables were evaluated through a semi-structured clinical interview and psychometric assessments. RESULTS: Plasma AEA concentrations were higher in patients with GD compared with HC (p = .002), without differences in 2-AG. AEA and 2-AG concentrations were related to GD severity, with novelty-seeking mediating relationships. CONCLUSIONS: This study points to differences in fasting plasma concentrations of endocannabinoids between individuals with GD and HC. In the clinical group, the pathway defined by the association between the concentrations of endocannabinoids and novelty-seeking predicted GD severity. Although exploratory, these results could contribute to the identification of potential endophenotypic features that help optimize personalized approaches to prevent and treat GD.

Effects of Mixing Energy Drinks With Alcohol on Driving-Related Skills.

BACKGROUND: Energy drinks (EDs) reduce sleepiness and fatigue and improve driving performance whereas alcohol does just the opposite. Although it is a trendy combination among young people, the effects of alcohol mixed with EDs on driving performance have been poorly studied. The aim was to assess if there is an interaction between the effects of both drinks on driving-related skills as well as perceptions about driving ability. METHODS: We conducted a randomized, double-blind, and placebo-controlled 4-way crossover clinical trial. Participants were 16 healthy volunteers. Interventions of 60 g of ethanol and 750 mL of Red Bull (RB) were administered in 2 separated doses. Conditions were alcohol + RB placebo, alcohol + RB, alcohol placebo + RB, and both placebos. Objective performance was assessed using a tracking test and simple reaction time, N-Back, and movement estimation tasks. Additionally, willingness to drive, other subjective effects, and ethanol and caffeine blood concentrations were also measured. RESULTS: Alcohol increased the time outside the road in the tracking test and increased simple reaction time, but the addition of RB had no main or interaction effects on performance. Nonetheless, driving-related skills after alcohol + RB were better than after alcohol alone. Willingness to drive increased with the combination of drinks. RB also reduced alcohol-induced sedation whereas drunkenness did not change. These effects were seen even though alcohol + RB increased alcohol (14.8%) and caffeine plasma concentrations (17.6%). CONCLUSIONS: Mixing EDs with alcohol predisposes consumers to drive under alcohol influence, perhaps in part because EDs counteract its detrimental effects on driving-related skills. Clinicaltrials.gov: NCT02771587.

Pharmacokinetics of maslinic and oleanolic acids from olive oil - Effects on endothelial function in healthy adults. A randomized, controlled, dose-response study.

To date, pharmacokinetics of maslinic (MA) and oleanolic (OA) acids, at normal dietary intakes in humans, have not been evaluated, and data concerning their bioactive effects are scarce. We assessed MA and OA pharmacokinetics after ingestion of olive oils (OOs) with high and low triterpenic acid contents, and specifically the effect of triterpenes on endothelial function. We performed a double-blind, dose-response, randomized, cross-over nutritional intervention in healthy adults, and observed that MA and OA increased in biological fluids in a dose-dependent manner. MA bioavailability was greater than that of OA, and consumption of pentacyclic triterpenes was associated with improved endothelial function. To the best of our knowledge, this is the first time MA pharmacokinetics, and effects on endothelial function in vivo, have been reported in humans.

Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure.

Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the most prominent active constituent of cannabis, alters neurodevelopmental plasticity with a long-term functional impact on adult offspring. Specifically, THC affects the development of pyramidal neurons and GABAergic interneurons via cannabinoid CB1 receptors (CB1R). However, the particular contribution of these two neuronal lineages to the behavioral alterations and functional deficits induced by THC is still unclear. Here, by using conditional CB1R knockout mice, we investigated the neurodevelopmental consequences of prenatal THC exposure in adulthood, as well as their potential sex differences. Adult mice that had been exposed to THC during embryonic development showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. Remarkably, we found a clear sexual dimorphism in these effects, with males being selectively affected. At the neuronal level, we found a striking interneuronopathy of CCK-containing interneurons in the hippocampus, which was restricted to male progeny. This THC-induced CCK-interneuron reduction was not evident in mice lacking CB1R selectively in GABAergic interneurons, thus pointing to a cell-autonomous THC action. In vivo electrophysiological recordings of hippocampal LFPs revealed alterations in hippocampal oscillations confined to the stratum pyramidale of CA1 in male offspring. In addition, sharp-wave ripples, a major high-frequency oscillation crucial for learning and memory consolidation, were also altered, pointing to aberrant circuitries caused by persistent reduction of CCK+ basket cells. Taken together, these findings provide a mechanistic explanation for the long-term interneuronopathy responsible for the sex-dimorphic cognitive impairment induced by prenatal THC.

Dose-Response Pharmacological Study of Mephedrone and Its Metabolites: Pharmacokinetics, Serotoninergic Effects, and Impact of CYP2D6 Genetic Variation.

Mephedrone (MEPH), the most widely consumed synthetic cathinone, has been associated with acute toxicity episodes. The aim of this report was to study its metabolic disposition and the impact of genetic variation of CYP2D6 on MEPH metabolism, in a dose range compatible with its recreational use. A randomized, crossover, phase I clinical trial was performed. Subjects received 50 and 100 mg (n = 3) and 150 and 200 mg (n = 6) of mephedrone and were genetically and phenotypically characterized for the CYP2D6 allelic variation. Our results showed a linear kinetics of mephedrone at the dose range assayed: plasma concentrations, cardiovascular and subjective effects, and blood serotonin concentrations all correlated in a dose-dependent manner. Mephedrone metabolic disposition is mediated by CYP2D6. Mephedrone pharmacology presented a linear dose-dependence within the range of doses tested. The metabolism of mephedrone by CYP2D6 implies that recreational users with no or low CYP2D6 functionality are exposed to unwanted acute toxicity episodes.

Short- and medium-term impact of bariatric surgery on the activities of CYP2D6, CYP3A4, CYP2C9, and CYP1A2 in morbid obesity.

Morbid obesity and bariatric surgery induce anatomical, physiological and metabolic alterations that may alter the body's disposition of drugs. Current literature on this topic is limited and sometimes inconsistent. Cytochrome P450 (CYP) is a superfamily of enzymes that metabolize around 75% of all marketed drugs. The purpose of this study was to evaluate the impact of body mass index and bariatric surgery on CYP activities. Firstly, we evaluated the in vivo activity of 4 major CYP isoenzymes (CYP2D6, CYP3A4, CYP2C9, and CYP1A2) in normal weight, overweight, and morbidly obese individuals. Secondly, we assessed the short- (1 month) and medium-term (6 month) effects of the most commonly employed bariatric surgery techniques (laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) on the activity of these enzymes. CYP3A4 activity was lower in morbidly obese individuals, compared to normal-weight controls. Interestingly, bariatric surgery normalized CYP3A4 activity. In comparison with normal-weight controls, morbidly obese individuals had higher CYP2D6 activity, which was only observed in individuals with two functional alleles for this isoenzyme. Neither body mass index nor surgery had significant effects on CYP2C9 and CYP1A2 activities. Overall, no relevant differences in CYP activities were found between surgical techniques. In conclusion, further studies should evaluate whether the observed alterations in CYP3A4 activity will require dose adjustments for CYP3A4 substrates especially in morbidly obese individuals before and after bariatric surgery.

Acute Pharmacological Effects of 2C-B in Humans: An Observational Study.

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2-3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.

Liquid chromatography tandem mass spectrometric determination of triterpenes in human fluids: Evaluation of markers of dietary intake of olive oil and metabolic disposition of oleanolic acid and maslinic acid in humans.

Olive oil is rich in several minor components like maslinic (MA) and oleanolic (OA) acids which have cardioprotective, antitumor, and anti-inflammatory properties. In order to assess the health benefits in humans provided by the olive oil triterpenes (MA and OA), suitable analytical methods able to quantify the low concentrations expected in human fluids are required. In this study, the LC-MS/MS quantification of both OA and MA in plasma and urine has been evaluated. The plasmatic method is based on the direct determination of the analytes. The urinary detection requires more sensitivity which was reached by derivatization with 2-picolylamine. Additionally, the urinary species present after MA and OA ingestion were evaluated by the direct detection of several phase II metabolites previously synthesized. Our results showed that OA is metabolized as both sulfate and glucuronide conjugates whereas MA is mainly excreted as glucuronide. Based on this information, the method for the urinary detection of MA and OA involved an enzymatic hydrolysis. Both plasmatic and urinary methods were validated with suitable precision and accuracy at all tested levels. Required sensitivity was achieved in both matrices. Up to our knowledge, this is the first method able to quantify the low concentration levels of triterpenes present in urine. Samples from two healthy volunteers who received virgin olive oils with different triterpenes content were analyzed. Some preliminary clues on the metabolic disposition of OA and MA after olive oil intake are provided.

Pharmacokinetics of Mephedrone and Its Metabolites in Human by LC-MS/MS.

Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of mephedrone, nor-mephedrone, N-succinyl-nor-mephedrone, 1'-dihydro-mephedrone, and 4'-carboxy-mephedrone. The method was validated in human plasma and urine and in rat brain homogenates. Six healthy male subjects, recreational users of new psychoactive substances, ingested 150 mg of mephedrone within the context of a clinical trial. 4'-Carboxy-mephedrone, followed by nor-mephedrone, was the most abundant metabolites found in plasma. Dihydro-mephedrone represented 10% of the amount of mephedrone in plasma and N-succinyl-nor-mephedrone was the metabolite eliminated with the longer half-life of 8.2 h. In urine, 4'-carboxy-mephedrone was the main metabolite excreted with amounts recovered being about 10 times those of mephedrone. Additionally, the validated method was used to test metabolite ability to cross the blood-brain barrier in vivo in rats with mephedrone and nor-mephedrone as the main active compounds present in the brain. The method described is useful for the determinations of mephedrone and metabolites in biological samples. Graphical Abstract ᅟ.

MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor.

Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol), which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled within-subject study was conducted including a single oral dose of MDMA (75 mg), combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg). Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS) 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations). Findings showed that MDMA induced a dissociative state but this effect was not counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential of MDMA.

Non-Linear Formation of EtG and FAEEs after Controlled Administration of Low to Moderate Doses of Ethanol.

AIMS: Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of alcohol that can be detected in conventional and non-conventional biological matrices for longer periods than alcohol. The aim was to describe the time courses of both biomarkers after ingestion of acute low-moderate doses of ethanol. METHODS: The study design was double-blind, randomized, crossover and controlled with placebo. Participants were distributed in three different cohorts: (a) Cohort-1: two doses of 18 and 30 g of ethanol and placebo were administered to 12 subjects; (b) Cohort-2: two doses of 6 and 12 g of ethanol and placebo were administered to six subjects and (c) Cohort-3: two doses of 24 and 42 g of ethanol and placebo were administered to six subjects. Each participant received two doses of ethanol and placebo. Plasma concentrations (0-6 h) of ethanol and specific FAEEs (palmitic, stearic, linoleic and oleic acid ethyl esters) and urinary concentrations of EtG (0-24 h) were measured. RESULTS: A dose-dependent increase in blood ethanol concentrations was observed. EtG excretion and FAEEs plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. Area under the curve (AUC0-6h) of ethanol concentrations showed a linear trend with non-oxidative metabolites' concentrations. CONCLUSION: The formation rate of ethanol non-oxidative biomarkers does not follow a linear trend, explained mainly by a disproportionate increase in AUC0-6h of ethanol concentrations in relation to dose. This observation should be taken into account when interpreting results in biological matrices in clinical and forensic settings. SHORT SUMMARY: A double-blind, randomized, crossover and controlled study was conducted administering ethanol (6-42 g). Ethyl glucuronide (EtG) excretion and fatty acid ethyl esters (FAEEs) plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. This observation should be taken into account when interpreting biomarker concentrations in clinical settings.

GC-MS Quantification Method for Mephedrone in Plasma and Urine: Application to Human Pharmacokinetics.

Increasing consumption has been observed among young people of new psychoactive substances, including synthetic cathinone derivatives. The most well known of these is mephedrone whose use has been related to acute intoxication and fatality. Several methods able to detect mephedrone have been reported, although to date, none have been applied to human pharmacokinetic studies in a controlled setting. We developed a gas chromatography-mass spectrometry technique for mephedrone quantification in human plasma and urine. Plasma after deproteinization and urine were submitted to a liquid-liquid extraction and derivatization of the extract with MSTFA prior to analysis. Calibration curves covered concentration ranges in plasma between 5 and 300 ng/mL and in urine between 20 and 1,500 ng/mL. The method has been successfully applied to biological samples obtained from a pilot clinical trial intended to evaluate the human pharmacology of mephedrone and its relative bioavailability and pharmacokinetics. Six healthy males were administered 150 mg of mephedrone by the oral route in a randomized, double-blind, cross-over controlled trial. Peak plasma concentration (Cmax = 122.6 ± 32.9 ng/mL) was reached at 1 hour (0.5-2 h) post-drug administration. Mephedrone showed a rapid elimination half-life (t1/2 = 2.2 h) compared to other psychostimulants. Less than 15% of the dose was excreted in urine as a free-form. Mephedrone concentrations displayed a relevant inter-subject variability.

Human Pharmacology of Mephedrone in Comparison with MDMA.

Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-methylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone and its relative abuse liability compared with MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects, and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being, and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentration values for mephedrone and MDMA peaked at 1.25 h and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 h and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by the users.

Metabolic disposition and biological significance of simple phenols of dietary origin: hydroxytyrosol and tyrosol.

Hydroxytyrosol and tyrosol are dietary phenolic compounds present in virgin olive oil and wine. Both compounds are also endogenously synthesized in our body as byproducts of dopamine and tyramine metabolisms, respectively. Over the last decades, research into hydroxytyrosol and tyrosol has experienced an increasing interest due to the role that these compounds may play in the prevention of certain pathologies (e.g. cardiovascular, metabolic, neurodegenerative diseases and cancer). The translation of promising in vitro and in vivo biological effects from preclinical studies to the context of human disease prevention initially depends on whether the dose ingested becomes available at the site of action. In this regard, information regarding the bioavailability and metabolic disposition of hydroxytyrosol and tyrosol is of most importance to evaluate the impact they may have on human health. In this review, we discuss and summarize the state of the art of the scientific evidence regarding the processes of absorption, distribution, metabolism and excretion of both hydroxytyrosol and tyrosol. We also examine the impact of these compounds and their metabolites on biological activity in terms of beneficial health effects. Finally, we evaluate the different analytical approaches that have been developed to measure the plasma and urinary levels of hydroxytyrosol, tyrosol and their metabolites.

Analysis of free hydroxytyrosol in human plasma following the administration of olive oil.

Hydroxytyrosol (HT) from olive oil, a potent bioactive molecule with health benefits, has a poor bioavailability, its free form (free HT) being undetectable so far. This fact leads to the controversy whether attained HT concentrations after olive oil polyphenol ingestion are too low to explain the observed biological activities. Due to this, an analytical methodology to determine free HT in plasma is crucial for understanding HT biological activity. Plasma HT instability and low concentrations have been major limitations for its quantification in clinical studies. Here, we describe a method to detect and quantify free HT in human plasma by using liquid chromatography coupled to tandem mass spectrometry. The method encompasses different steps of sample preparation including plasma stabilization, protein precipitation, selective derivatization with benzylamine, and purification by solid-phase extraction. A high sensitivity (LOD, 0.3ng/mL), specificity and stability of HT is achieved following these procedures. The method was validated and its applicability was demonstrated by analyzing human plasma samples after olive oil intake. A pharmacokinetic comparison was performed measuring free HT plasma concentrations following the intake of 25mL of ordinary olive oil (nearly undetectable concentrations) versus an extra-virgin olive oil (Cmax=4.40ng/mL). To our knowledge, this is the first time that an analytical procedure for quantifying free HT in plasma after olive oil dietary doses has been reported. The present methodology opens the door to a better understanding of the relationship between HT plasma concentrations and its beneficial health effects.

Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

Ethanol induces hydroxytyrosol formation in humans.

Previous studies in animals have shown an increase of hydroxytyrosol (OHTyr), a potent phenolic antioxidant and a minor metabolite of dopamine (also called 3,4-dihydroxyphenylethanol or DOPET), after ethanol intake. The interaction between ethanol and dopamine metabolism is the probable mechanism involved. The aim of the study was to establish the contribution of the dose of ethanol on OHTyr formation. 24 healthy male volunteers were included. Subjects were distributed in three different cohorts and each volunteer received two doses of ethanol or placebo. Doses of ethanol administered were 6, 12, 18, 24, 30 and 42 g. Study design was double-blind, randomized, crossover and controlled. Hydroxytyrosol, tyrosol (Tyr), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) urinary excretion, ethanol plasma concentrations and drunkenness were evaluated along a 6-h period. Urinary excretion of OHTyr and Tyr increased with ethanol administered dose. A reduction in the ratio DOPAC/OHTyr from placebo to the highest dose was observed, compatible with a shift in the dopamine metabolism to preferently produce OHTyr instead of DOPAC. Also a dose-dependent increase in plasma ethanol concentrations and subjective effects was observed. This study demonstrates an endogenous production of OHTyr and Tyr in relation to ethanol administered dose in humans. Biological effects of both phenols from this source should be investigated in future studies.

Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial.

In humans, urinary hydroxytyrosol (OHTyr) concentrations have been associated to alcohol and wine consumption. To explore the role of wine components on promoting an endogenous OHTyr generation we performed a cross-over, double-blind, randomized controlled clinical trial (n = 28 healthy volunteers). Ethanol (wine and vodka), dealcoholized wine, and placebo were administered. Alcohol, dealcoholized wine, and particularly wine promoted a de novo OHTyr generation in vivo in humans. Potential OHTyr precursors (tyrosine, tyrosol, tyramine) were investigated in rats. Tyrosol was metabolized to OHTyr. Collating both studies, it is postulated that an increased Tyr bioavailability, a shift to a reductive pathway in dopamine and tyramine oxidative metabolism, and the biotransformation of Tyr to OHTyr were mechanisms involved in the OHTyr endogenous generation.

Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans.

SCOPE: Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. METHODS AND RESULTS: Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study. CONCLUSION: We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

Evaluation of plasma-free endocannabinoids and their congeners in abstinent cocaine addicts seeking outpatient treatment: impact of psychiatric co-morbidity.

Cocaine is associated with serious health problems including psychiatric co-morbidity. There is a need for the identification of biomarkers for the stratification of cocaine-addicted subjects. Several studies have evaluated circulating endocannabinoid-related lipids as biomarkers of inflammatory, metabolic and mental disorders. However, little is known in substance use disorders. This study characterizes both free N-acyl-ethanolamines (NAEs) and 2-acyl-glycerols in abstinent cocaine addicts from outpatient treatment programs who were diagnosed with cocaine use disorder (CUD; n = 88), and age-/gender-/body mass-matched healthy control volunteers (n = 46). Substance and mental disorders that commonly occur with substance abuse were assessed by the semi-structured interview 'Psychiatric Research Interview for Substance and Mental Diseases' according to the 'Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision' (DSM-IV-TR) and plasma-free acyl derivatives were quantified by a liquid chromatography-tandem mass spectrometry system. The results indicate that plasma acyl derivatives are altered in abstinent cocaine-addicted subjects with CUD (CUD subjects). While NAEs were found to be increased, 2-acyl-glycerols were decreased in CUD subjects compared with controls. Multivariate predictive models based on these lipids as explanatory variables were developed to distinguish CUD subjects from controls providing high discriminatory power. However, these alterations were not influenced by the DSM-IV-TR criteria for cocaine abuse and dependence as cocaine trait severity measure. In contrast, we observed that some free acyl derivatives in CUD subjects were found to be affected by the diagnosis of some co-morbid psychiatric disorders. Thus, we found that the monounsaturated NAEs were significantly elevated in CUD subjects diagnosed with mood [N-oleoyl-ethanolamine and N-palmitoleoyl-ethanolamine (POEA)] and anxiety (POEA) disorders compared with non-co-morbid CUD subjects. Interestingly, the coexistence of alcohol use disorders did not influence the circulating levels of these free acyl derivatives. In summary, we have identified plasma-free acyl derivatives that might serve as reliable biomarkers for CUD. Furthermore, we found that monounsaturated NAE levels are also enhanced by co-morbid mood and anxiety disorders in cocaine addicts. These findings open the way for the development of new strategies for cocaine addiction diagnosis and treatment.