Biomarkers of the alcohol hangover state: Ethyl glucuronide (EtG) and ethyl sulfate (EtS).

INTRODUCTION: The aim of this study was to investigate the usefulness of ethyl glucuronide (EtG) and ethyl sulfate (EtS) as biomarkers of the hangover state. METHODS: Thirty-sixhealthy social drinkers participated in this study, being of naturalistic design. Eighteen participants experience regular hangovers (the hangover group), whereas the other 18 claim to not experience a hangover (the hangover-immune group). On a control day (alcohol-free) day and a post-alcohol day, urine EtG and EtS concentrations were determined and hangover severity assessed. RESULTS: Urinary EtG and EtS concentrations were significantly increased on post-alcohol day compared to the control day (p = .0001). Both EtG and EtS concentrations did not significantly correlate with the overall hangover score, nor with the estimated peak blood alcohol concentrations and number of alcoholic drinks. EtG correlated significantly only with the individual hangover symptom "headache" (p = .033; r = .403). No significant correlations were found with the EtG to EtS ratio. EtG and EtS concentrations significantly correlated with urine ethanol concentrations. CONCLUSIONS: Although urine EtG and EtS concentration did not significantly correlate to estimated peak blood alcohol concentrations or the number of alcoholic drinks consumed, a significant correlation was found with urine ethanol concentration. However, urine EtG and EtS concentrations did not significantly correlate with overall hangover severity.

Preliminary investigations on ethyl glucuronide and ethyl sulfate cutoffs for detecting alcohol consumption on the basis of an ingestion experiment and on data from withdrawal treatment.

Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are commonly used alcohol markers for previous alcohol consumption. Nevertheless, the optimum EtG cutoff for urinary abstinence tests is still being discussed, and no cutoff has been recommended for EtS yet. The aim of this study was to verify cutoffs by investigating EtG and EtS concentrations (c(EtG) and c(EtS)) in the urine of healthy persons after drinking small, but realistic amounts of alcohol (one or two glasses of beer or white wine), and to look for the window of detection in strongly alcohol-intoxicated patients who were beginning withdrawal treatment. Very high EtG and EtS concentrations were measured in the first urine samples of patients under withdrawal treatment. However, 24 h later, concentrations decreased considerably, and c (EtG) < 0.5 mg/l and c (EtS) < 0.1 mg/l were determined in 26.7 % (4/13) and 13.3 % (2/13) of the samples, respectively. Concentrations above 0.1 mg/l (EtG) and 0.05 mg/l (EtS) were measured for 23.5 and 20.5 h after consuming 0.1 l of white wine or 0.33 l of beer, and 24 h after the experiment, 75 % (9/12) of the urine samples were tested negative for EtG and EtS using the following cutoffs: EtG 0.5 mg/l and EtS 0.1 mg/l. In half of the samples, concentrations below 0.1 mg/l (EtG) and 0.05 mg/l (EtS) were detected. Urinary cutoffs for EtG of 0.5 mg/l or higher are not suitable for testing abstinence. Even 0.1 mg/l is not effective to detect the intake of small amounts of alcohol in the context of abstinence tests. For EtS, 0.05 mg/l were found to be a potential cutoff to exclude the repeated intake of alcohol. Yet, further research is required to verify this cutoff. For a limited time period, EtG and EtS concentrations within the range of these cutoffs are also detectable after unintentional consumption of alcohol. Participants of abstinence programs have to be informed about the alcohol content of certain foods and beverages whose consumption is in conflict with strict abstinence.

Desmopressin accelerates the rate of urinary morphine excretion and attenuates withdrawal symptoms in rats.

AIM: The aim of this study was to examine the effects of desmopressin on morphine withdrawal symptoms and vasopressin level in morphine-dependent subjects. METHODS: Wistar male rats were injected s.c. with morphine once per day for 5 consecutive days to induce morphine dependence. After morphine use ceased on day 5, an equal number of rats were assigned to one of four groups for either saline or desmopressin by either intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection. From days 5 to 10, urine was collected daily and tested for the presence of morphine, and withdrawal symptoms were monitored to assess the effects of desmopressin. RESULTS: Significant weight loss occurred among all morphine-addicted rats during the withdrawal period. With both methods (i.p. and i.c.v.), the period of urinary morphine excretion was shorter for the two groups that were given desmopressin (experimental groups) than the two groups that were not given desmopressin (control groups), and no significant difference in urinary morphine excretion was found between the two experimental groups. During the early stage of withdrawal, the severity of the withdrawal symptoms in the experimental groups was significantly lower than that in the control groups. CONCLUSION: Desmopressin decreases the extent of morphine withdrawal symptoms, indicating that this agent might be appropriate for treating morphine addiction. Desmopressin appears to reduce withdrawal symptoms not by exerting an anti-diuretic effect but rather by exerting an effect on the central nervous system.

Dopamine-related tetrahydroisoquinolines: significant urinary excretion by alcoholics after alcohol consumption.

Concentrations of dopamine-related tetrahydroisoquinolines (salsolinol and O-methylated salsolinol) were significantly higher in the daily urine samples of alcoholic subjects admitted for alcohol detoxification than in the daily urine samples of nonalcoholic control subjects. Salsolinol concentrations in alcoholic subjects appeared to drop to trace (control) values 2 to 3 days after admission, following the disappearance of ethanol and its reactive metabolite acetaldehyde from the blood. These results indicate that physiologically active tetrahydroisoquinolines increase in humans during long-term alcohol consumption, presumably because of acetaldehyde's direct condensation with catecholamines. The presence of these or similar condensation products in the urine could be useful as clinical indicators of prior blood acetaldehyde concentrations in chronic alcoholics.

Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study.

Cannabis is the most widely used illicit substance in the world. Estimates suggest that approximately 10-20% of cannabis users meet criteria for cannabis dependence and a significant proportion experience withdrawal discomfort on cessation of use. To date, there has been an absence of any clinically validated treatments to manage withdrawal. The current study is an open-label trial exploring the utility of lithium carbonate for the management of cannabis withdrawal symptoms in treatment seeking adult humans. In total, 20 participants were recruited to the study (19 men). All met DSM-IV cannabis-dependence criteria and had been smoking cannabis daily or almost daily for a mean 9 years. Participants were admitted to an inpatient detoxification facility and prescribed lithium 500 mg b.d. for 7 days. Cannabis withdrawal was assessed daily with the Marijuana Withdrawal Checklist (MWC). Two participants were withdrawn from the trial because of possible adverse effects. Sixty percent of participants completed the 7-day treatment program. Follow-up was conducted at a mean of 107 days following treatment. The mean percentage of days abstinent in the period between treatment cessation and follow-up was 87.57%. Twenty-nine percent of participants (n=5) reported continuous abstinence that was biochemically verified at follow-up. Agreement between self-reported cannabis use and urinalysis at follow-up was moderate (kappa=0.47). Significant reductions in symptoms of depression and anxiety and cannabis-related problems were also reported. This study provides evidence for the potential clinical utility and safety of lithium in the management of cannabis withdrawal. A randomised, placebo-controlled trial is recommended.

Ethylglucuronide determination in urine and hair from alcohol withdrawal patients.

Two methods for the determination of ethylglucuronide (EtG) in urine and in hair have been developed by liquid chromatography- tandem mass spectrometry. These two methods were fully validated, including linearity (0.25-100 microg/mL in urine; 0.05-5 ng/mg in hair; r(2) > 0.99, n = 5), limits of detection (0.1 microg/mL in urine, 0.025 ng/mg in hair) and quantitation (lowest level of the calibration curve), extraction efficiency (> 55%), within-day and between-day imprecision and bias (CV and mean relative error < 15%), matrix effect, and relative ion intensity. These methods have been applied to 541 urine samples and 17 hair specimens collected from 156 alcohol withdrawal patients. The determination of ethanol versus EtG in urine was compared, and also the convenience of EtG determination in hair. EtG in urine and in hair proved to be a powerful tool for monitoring abstinence in these patients.

Making risky decisions to take drug: Effects of cocaine abstinence in cocaine users.

Risky decision-making is characteristic of drug users, but little is known about the effects of circumstances, such as abstinence, on risky choice behavior in human drug users. We hypothesized that cocaine users would make more risky choices for cocaine (defined as taking a chance to receive a large number of cocaine doses as opposed to choosing to receive a fixed amount of cocaine) after 3 or 7 days of cocaine abstinence, compared to 1 day of cocaine abstinence. Six male nontreatment-seeking current cocaine smokers were enrolled in a 21-day inpatient within-subject study. Participants repeatedly smoked six 25 mg doses of cocaine during a training session and were instructed that they would be making decisions about smoking this dose throughout the study. After 1, 3 and 7 days of cocaine abstinence, participants completed a computerized task in which they repeatedly decided between receiving a guaranteed number of cocaine doses (between 1 and 5; fixed option) or receiving a chance (0.13 to 0.75) to smoke a larger number of cocaine doses (probabilistic option). After completing the computerized task, one of the participants' choices was randomly implemented and they smoked either the fixed number of cocaine doses or had the specified chance to smoke the greater number of doses. Contrary to our hypothesis, 5 of the 6 participants made fewer risky choices after 3 and 7 days of cocaine abstinence compared to one day of abstinence suggesting greater risk-aversion. Thus, even during cocaine abstinence cocaine users make rational decisions related to their drug use.

A brief abstinence test for college student smokers: a feasibility study.

Cigarette smoking among college students is prevalent and correlated with other unhealthy behaviors. Reinforced abstinence (e.g., contingency management) has been demonstrated to be an effective method for reducing substance use in a variety of populations and across a variety of drugs, including cigarettes. Reinforced abstinence has seldom been used specifically targeting a college student population. A Brief Abstinence Test (BAT) has been used to effectively reduce cocaine use among methadone maintenance patients (Robles, Silverman, Preston, Cone, Katz, Bigelow, & Stitzer, 2000). However, no published studies have investigated the use of a BAT to reduce the use of cigarettes. The current study implemented a 3-week intervention (Baseline 1, BAT, and Baseline 2 weeks) for smoking abstinence among college students. Forty-two percent of the sample met abstention criteria during the BAT. Carbon monoxide and urinalysis scores decreased significantly from Baseline 1 to the BAT phase but did not differ significantly from BAT to Baseline 2. These results suggest that the BAT may have utility initiating abstinence in both clinical and research contexts.

Abrupt alcohol withdrawal: another cause of ketoacidosis often forgotten.

A 54-year-old woman was admitted to our emergency department for acute confusion. She had only a history of chronic alcohol abuse with an abrupt withdrawal. The initial diagnosis was delirium tremens. Biological findings, however, showed a severe degree of metabolic acidosis (plasma pH 7.07, bicarbonate 9.6 mmol/l) with an increased anion gap (39.6 mmol/l). Serum glucose was normal and ketonuria was present. Ketoacidosis was also suspected and treated by fluid infusion and delivery of glucose with a favorable outcome. Differential ketoacidosis is discussed in the emergency room.

Biotin dependency due to a defect in biotin transport.

We describe a 3-year-old boy with biotin dependency not caused by biotinidase, holocarboxylase synthetase, or nutritional biotin deficiency. We sought to define the mechanism of his biotin dependency. The child became acutely encephalopathic at age 18 months. Urinary organic acids indicated deficiency of several biotin-dependent carboxylases. Symptoms improved rapidly following biotin supplementation. Serum biotinidase activity and Biotinidase gene sequence were normal. Activities of biotin-dependent carboxylases in PBMCs and cultured skin fibroblasts were normal, excluding biotin holocarboxylase synthetase deficiency. Despite extracellular biotin sufficiency, biotin withdrawal caused recurrent abnormal organic aciduria, indicating intracellular biotin deficiency. Biotin uptake rates into fresh PBMCs from the child and into his PBMCs transformed with Epstein Barr virus were about 10% of normal fresh and transformed control cells, respectively. For fresh and transformed PBMCs from his parents, biotin uptake rates were consistent with heterozygosity for an autosomal recessive genetic defect. Increased biotin breakdown was ruled out, as were artifacts of biotin supplementation and generalized defects in membrane permeability for biotin. These results provide evidence for a novel genetic defect in biotin transport. This child is the first known with this defect, which should now be included in the identified causes of biotin dependency.

Ecstasy (MDMA) does not have long-term effects on aggressive interpretative bias: a study comparing current and ex-ecstasy users with polydrug and drug-naive controls.

+/-3, 4-methylenedioxymethamphetamine (MDMA or ecstasy) remains a widely used recreational drug, which, in animals, can produce long-lasting changes to the brain's serotonergic system. As serotonin has been implicated in human aggression, it is possible that ecstasy users are at risk of increased aggression even after prolonged abstention from the drug. The objective of this study was to indirectly assess aggression in current and abstinent ecstasy users using an information-processing paradigm that measures cognitive bias toward material with aggressive content. The task employed has previously shown increased aggressive bias 3-4 days after ecstasy use. An interpretative bias task was administered to 105 male participants: 26 ex-ecstasy users, 25 current ecstasy users, 29 polydrug using controls, and 25 drug-naive controls. Accuracy and response times to process and recognize ambiguous sentences were tested. There were no group differences in aggressive interpretative bias. All 4 groups processed neutral sentences faster than aggressive sentences and were subsequently faster and more confident in recognizing neutral compared with aggressive sentences. Further, self-ratings of aggression also showed no group differences, even though self-rated impulsivity was significantly higher in current ecstasy users than in drug-naive controls. The findings that all groups were biased toward neutral and away from aggressive interpretations of ambiguous sentences add to the existing body of knowledge in suggesting that increased aggression found in ecstasy users a few days after taking the drug is a transient phenomenon and not a long-term, persisting effect.

Excretion of catecholamine metabolites during methadone maintenance and withdrawal.

Catecholamine metabolites excreted by long-term methadone hydrochloride-dependent subjects were studied in a protocol involving a two-study design. After a two-week methadone maintenance period, 15 subjects underwent abrupt methadone withdrawal and 12 subjects, gradual methadone withdrawal. The first study compared levels of catecholamine metabolites excreted during the stable methadone period with those excreted during the abrupt withdrawal period, as well as with those eliminated by healthy nonaddicted controls. No changes in the excretion of 3-methoxy-4-hydroxyphenylglycol and normetanephrine were noted between the methadone maintenance period and the time of abrupt methadone withdrawal. These values did not differ from those obtained for controls. However, higher levels of metanephreine were excreted during the stable methadone period than those in controls. During withdrawal, levels of metanephrine dropped a statistically significant amount in comparison with levels observed during the stable methadone period. The gradual withdrawal study confirmed these findings.

Marijuana abstinence effects in marijuana smokers maintained in their home environment.

BACKGROUND: Although withdrawal symptoms are commonly reported by persons seeking treatment for marijuana dependence, the validity and clinical significance of a marijuana withdrawal syndrome has not been established. This controlled outpatient study examined the reliability and specificity of the abstinence effects that occur when daily marijuana users abruptly stop smoking marijuana. METHODS: Twelve daily marijuana smokers were assessed on 16 consecutive days during which they smoked marijuana as usual (days 1-5), abstained from smoking marijuana (days 6-8), returned to smoking marijuana (days 9-13), and again abstained from smoking marijuana (days 14-16). RESULTS: An overall measure of withdrawal discomfort increased significantly during the abstinence phases and returned to baseline when marijuana smoking resumed. Craving for marijuana, decreased appetite, sleep difficulty, and weight loss reliably changed across the smoking and abstinence phases. Aggression, anger, irritability, restlessness, and strange dreams increased significantly during one abstinence phase, but not the other. Collateral observers confirmed participant reports of these symptoms. CONCLUSIONS: This study validated several specific effects of marijuana abstinence in heavy marijuana users, and showed they were reliable and clinically significant. These withdrawal effects appear similar in type and magnitude to those observed in studies of nicotine withdrawal.

Significance of spontaneous ketonuria and serum C-peptide levels in obese type II diabetic patients.

Patients with type II diabetes mellitus (type II DM patients) are characteristically obese, hyperinsulinemic, and non-ketosis prone. Recently, we have encountered several obese type II DM patients with either diabetic ketoacidosis or significant ketonuria after insulin withdrawal. There was no evidence of infection, stress, or starvation to explain their ketonuria. Therefore, we assessed serum connecting peptide (C-peptide) response to oral glucose in 14 obese, insulin-treated type II DM patients: 6 with and 8 without episodes of spontaneous ketonuria. The group presenting with ketonuria had low to absent basal and stimulated serum C-peptide responses. The nonketonuric group had higher basal C-peptide (P less than 0.01) concentrations that increased significantly (P less than 0.001) after oral glucose compared with those of the ketonuric group. Clinical characteristics and biochemical control were similar in both groups. Our findings confirm that obese type II diabetes mellitus is a heterogeneous disease with variable fasting and stimulated C-peptide responses. Spontaneous ketonuria could be a feature in the clinical presentation of the patients especially in the presence of both low fasting and stimulated C-peptide levels. The significance of these findings is unclear but suggests individualization in the management of type II DM patients and cautious withdrawal of insulin therapy in such patients. Furthermore, serum C-peptide levels alone cannot be recommended to classify patients into either type I or type II diabetes mellitus.

Monoamine metabolism during chronic benzodiazepine treatment and withdrawal.

Long-term normal-dose benzodiazepine treatment in seven patients was associated with reduced urinary excretion of MOPEG (4-hydroxy-3-methoxy-phenylglycol). Following the discontinuation of the drugs a characteristic withdrawal reaction occurred, with an increase towards normal values of the MOPEG excretion levels and changes in the excretion of 5-HIAA (5-hydroxyindoleacetic acid). No significant changes in the 24-hr urinary excretion of free cortisol or HMMA (3-methoxy-hydroxy-mandelic acid) were detected.

Lithium treatment during alcoholic withdrawal.

The efficacy of lithium carbonate was studied in 18 chronic alcoholic male patients in withdrawal. In mild alcoholic withdrawal, oral lithium carbonate, 0.3 gm every 8 hr, diminishes subjective symptoms of withdrawal and normalizes performance on a motor tracking task. Patients who start lithium while drinking ethanol improve most probably because it takes longer than 3 days for lithium concentrations in the blood to plateau. Lithium does not importantly alter patterns of catecholamine excretion, blood pressures, heart rate, serum cyclic-adenosine monophosphate (AMP), serum dopamine beta-hydroxylase (DBH), sleep pattern, or tremor amplitude during withdrawal.

Urinary amine metabolite excretion in a patient with adrenergic hyperactivity state: reaction to phenelzine withdrawal and combined treatment.

Urinary MHPG (3-methoxy-4-hydroxyphenylglycol) amounts increased threefold during a toxic delirious state in a 57-year-old bipolar patient 3 days after phenelzine treatment was stopped. This norepinephrine metabolite was not expected to rise as monoamine oxidase (MAO) was completely blocked. In addition, the delirious state appeared as a rebound phenomenon and not an acute toxic state during drug administration. It seems that phenelzine acts more through catecholamine release phenomenon than by inhibition of MAO.

Urinary adrenaline concentrations during 10 days of smoking abstinence.

Urinary adrenaline concentrations were measured in 17 subjects during 10 days of cigarette abstinence. Adrenaline concentrations dropped significantly in the first 3 days of cigarette withdrawal. This was followed by a significant rise. More subjects showed a U-shaped function of adrenaline over time than would be expected by chance. The evidence suggests that the drop in urinary adrenaline concentration following cigarette withdrawal does not merely constitute a return to a non-smoking state, but includes an element of rebound resulting from loss of a component of smoking, probably nicotine, to which adaptation has occurred.

Urinary cyclic AMP excretion by methadone subjects during gradual and acute withdrawal.

Laboratory and animal investigations have supported the hypothesis that levels of cyclic AMP are stable during tolerance to narcotic drugs and increased during withdrawal. In order to test this hypothesis, serial 24-h urinary excretion of cyclic AMP by long-term methadone addicts was determined during a period of stable methadone intake, a period of gradual withdrawal, and a period of acute withdrawal. Cyclic AMP excretion during stable methadone intake is identical to that of normal control subjects. Neither gradual nor acute withdrawal appears to affect the urinary excretion of cyclic AMP. These data agree with previous reports in the literature which suggest that cyclic AMP levels are not altered during tolerance to narcotics, but do not support the hypothesis that levels of the nucleotide might be increased during withdrawal.