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.

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.

Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure.

This pilot study examined the efficacy of the N-type calcium channel blocker gabapentin to improve outcomes during a brief detoxification protocol with buprenorphine. Treatment-seeking opioid-dependent individuals were enrolled in a 5-week, double-blind, placebo-controlled trial examining the effects of gabapentin during a 10-day outpatient detoxification from buprenorphine. Participants were inducted onto buprenorphine sublingual tablets during Week 1, were randomized and inducted onto gabapentin or placebo during Week 2, underwent a 10-day buprenorphine taper during Weeks 3 and 4, and then were tapered off gabapentin/placebo during Week 5. Assessments included thrice-weekly opioid withdrawal scales, vitals, and urine drug screens. Twenty-four individuals (13 male; 17 Caucasian, 3 African American, 4 Latino; mean age 29.7 years) participated in the detoxification portion of the study (gabapentin, n = 11; placebo, n = 13). Baseline characteristics did not differ significantly between groups. Self-reported and observer-rated opioid withdrawal ratings were relatively low and did not differ between groups during the buprenorphine taper. Urine results showed a Drug × Time interaction, such that the probability of opioid-positive urines significantly decreased over time in the gabapentin versus placebo groups during Weeks 3 and 4 (OR = 0.73, p = .004). These results suggest that gabapentin reduces opioid use during a 10-day buprenorphine detoxification procedure.

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.

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.

Effects of 21 days of varenicline versus placebo on smoking behaviors and urges among non-treatment seeking smokers.

Varenicline promotes smoking cessation and reduces urges to smoke. However, the mechanisms associated with these effects and their time course are not well characterized. One mechanism may be extinction, but the duration of the current dosing protocol may not be sufficient. We examined the effect of extended pre-treatment with varenicline on smoking behavior among 17 non-treatment seeking adult smokers. Using a within-subjects, double-blind, placebo-controlled crossover design, participants received standard dosing of varenicline for 21 days, followed by a 14-day washout period and 21 days of placebo; order counterbalanced. Cigarettes per day (CPD), smoking topography, smoking urges (QSU), and side effects were assessed every three days. Biomarkers (e.g. nicotine metabolites) were collected on days 1, 7, and 21. There was a significant drug by time interaction indicating a reduction in CPD during varenicline phase (between days 10-21), but no reduction during placebo. Varenicline also led to reductions in nicotine metabolites and urges to smoke. Among this sample of non-treatment seeking smokers, varenicline significantly reduced smoking behavior. Results have important treatment implications because changes in CPD and craving did not occur until after the typical one-week run-up period. This suggests that a longer duration of pre-treatment may be beneficial for some smokers.

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.

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.

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.

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.

A randomized trial of one-day vs. three-day buprenorphine inpatient detoxification protocols for heroin dependence.

Detoxification from opioids remains an important first step in the treatment of many patients with opioid dependence. Several pharmacologic regimens have been used for opioid detoxification. In the United States, the partial mu-opioid agonist, buprenorphine (BUP) is the most recently approved pharmacotherapy for opioid detoxification and replacement. The literature in recent years has described detoxification protocols using a single high dose of BUP and a three-day BUP regimen. In many settings, such as drug-free programs, a single-dose detoxification protocol would be of significant benefit. There have been no prior studies comparing one-day and three-day BUP-assisted opioid withdrawal. In this pilot study, we conducted an open-label, randomized trial of one-day vs. three-day BUP/naloxone sublingual tablet-assisted opioid withdrawal. Twenty patients from a therapeutic community treatment program were randomly assigned to receive either 32 mg sublingual BUP over one hour (one-day group), or 32 mg sublingual BUP over three days (three-day group). Nine of 10 subjects (90 percent) in each group completed seven days in the detoxification protocol. There was no statistically significant difference between the two groups in all other outcome variables, including retention in the treatment program, intensity of withdrawal signs and symptoms, amounts of adjunct medications used, and ability to produce opiate-free urine. This study further validates the feasibility of the single high dose of BUP as a rapid detoxification method.

[Effect of glutaminic acid on the activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of development of the alcohol abstinence syndrome]. / Vplyv hlutaminovoï kysloty na aktyvnist' sympatyko-adrenalovoï systemy i vmist kal'tsiiu v sechi dynamitsi formuvannia alkohol'noho abstynentnoho syndromu.

The paper deals with the influence of glutaminic acid on the functional activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of the alcoholic abstinence syndrome development. Changes in the functional activity of sympatho-adrenal system and in the concentration of calcium in the process of the abstinence syndrome development are shown to be of the phase character. It is established that in the period of the developed abstinence syndrome glutaminic acid produces a normalizing action on the excretion of adrenaline and dopamine and also facilitates a decrease in the level of calcium in urine.

Psychosis related to ephedra-containing herbal supplement use.

Ephedra, a psychoactive substance with stimulant properties, is found in many herbal products. Often perceived by the lay public as benign, the potential health-related dangers of using these products are beginning to be recognized. We review four cases associated with ephedra-containing herbal products and report three additional cases. Unlike the previously reported cases, the patients presented in this report developed persistent psychosis that required psychopharmaceutical management.

Predictive factors of persisting illicit drug use in hospitalized heroin addicts.

The efficacy of methadone treatment in reducing the rate of positive urinalyses for opiates has been repeatedly assessed in outpatient intravenous heroin users (IHUs), but not in IHUs hospitalized for coexisting diseases. The aim of the present study, performed on 83 IHUs, was to assess the rate of drug-free urinalyses for addictive drugs over a 13-day period of hospitalization. The rate of drug-free urinalyses was then related to the intensity of withdrawal symptoms, the level of dependence (as measured by the severity of dependence scale (SDS)) and of heroin craving (as measured by a visual analogical scale, (VAS)), assessed on admission and on days 4, 7, 10, and 13. All but nine patients received methadone upon hospitalization. The results show that positive urinalyses for morphine and/or cocaine dropped over the period of observation from 67 to 7%. On admission, patients who persisted in the illicit use of heroin did not differ significantly from the rest in terms of abstinence scores or daily methadone dose, but scored higher at the SDS and yielded urinalyses which all tested positive for morphine and/or cocaine. In conclusion, in the hospital setting low methadone doses (32.5 mg per die on average) induce a drug-free condition in the majority of patients and high SDS scores associated with positive urinalysis for morphine and/or cocaine are predictive of persistent drug abuse during hospitalization.

Sulphatoxymelatonin excretion during opiate withdrawal: a preliminary study.

The excretion of sulphatoxymelatonin (aMT6S), a major metabolite of melatonin in urine, is dependent on noradrenergic (NA) neuronal activity within the pineal gland and thus represents a neuroendocrine marker of NA neuronal function. Many of the clinical features of opiate withdrawal result from increased firing of central NA neurones. In this study, we test the hypothesis that aMT6S excretion is increased during opiate withdrawal in opiate-dependent patients. The 24-h urinary aMT6S excretion was measured at three time points during in-patient methadone detoxification treatment in 11 opiate-dependent patients, during methadone stabilisation and on Days 6 and 12 of withdrawal treatment. There was a significant increase in aMT6S excretion on Day 6 but not on Day 12, compared to stabilisation. A significant correlation between individual withdrawal symptom score severity and aMT6S excretion was demonstrated during stabilisation (r=.68, P<.05) and on Day 6 of treatment (r=.62, P<.05). Our preliminary findings suggest that melatonin secretion may represent a neuroendocrine marker of NA neuronal hyperactivity during opiate withdrawal in opiate-dependent patients. Areas of future research are discussed.

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.

Ethyl glucuronide: on the time course of excretion in urine during detoxification.

Ethyl glucuronide (EtG) is a promising new biological state marker of recent alcohol consumption that detects alcohol use reliably over a definite time period. Other currently available markers lack acceptable sensitivity and specificity. Our aim is to elucidate under naturalistic conditions the time course of EtG excretion in urine following alcohol consumption and to show how this can be utilized for monitoring and prognosis in patients. There are no other existing data on this issue to date. One hundred and thirty-eight urine samples from 28 male alcohol withdrawal patients were drawn every 3-24 hours for up to 94 hours after hospitalization. Breath ethanol concentration (mean) at hospitalization was 900 mg/L. Patient age in years was 40.3 (mean). Determination of urine EtG was performed by gas chromatography/mass spectrometry (GC/MS) with deuterium-labelled EtG as an internal standard. The strongest correlations (p<0.01) were found between EtG determinations in the different patient when breath ethanol concentrations (BEC) were 0 and 48 hours after BEC=0 (r=0.747), EtG 24 and 48 hours after BEC=0 (r=0.872), and in the time frame of detection (hours) of EtG and EtG 48 hours after BEC=0 (r=0.762). No significant correlation was found (Mann-Whitney test) between EtG concentrations in urine at different time points between the groups of patients with (a) 1 or less-2, (b) 3-4 or more previous hospitalizations, (c) a history of seizures (yes/no) or (d) an age above or below the median (40.5). EtG excretion in urine is not random, but seems rather to follow a kinetic profile. Furthermore our preliminary data indicate, that there is no significant difference for EtG concentration in urine when correlated to group variables such as age, seizures and hospitalizations.

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.