Treatment retention and reductions in blood alcohol concentration (BAC) during the first 90 days of a telehealth program for alcohol use disorder.

Background: Alcohol use disorder (AUD) treatments, including medications, are increasingly offered via telehealth.Objective: This study characterizes 90-day treatment retention and changes in objectively measured blood alcohol concentration (BAC) in a large cohort receiving AUD telehealth.Methods: Patients received AUD treatment through Ria, a virtual (telehealth) program offering AUD treatment that is tailored to patient goals (e.g. abstinence or controlled drinking). Patients were encouraged to complete breathalyzer readings twice daily for measurement-based care. We characterized rates of 90-day treatment retention (i.e. completing a BAC reading or medical/coaching encounter on the 90th day or later) and used growth curve analyses to model changes in daily estimated peak BAC over 90 days.Results: Of 4121 patients (51.5% women), 50.1% had 90-day treatment retention (n = 2066, 52.2% women). Most patients received prescriptions for AUD medications (84.6%) and completed encounters with medical providers (86.7%) and coaches (86.1%). Patients with 90-day retention provided 184,817 BAC readings in the first 90 days. Growth curve analyses revealed significant reductions in daily estimated peak BAC (p < .001) from a mean of 0.092 (day 1) to 0.038 (day 90). Similar magnitudes of BAC reduction were observed for men and women and for patients with abstinence and controlled drinking goals.Conclusion: Telehealth appears to be a viable approach to delivering AUD treatments in a manner that promotes drinking reductions. Telehealth approaches can yield reductions in objectively measured BAC, including for some patient subgroups that have historically faced greater stigma in AUD treatment settings, such as women and people with non-abstinence drinking goals.

A novel telehealth platform for alcohol use disorder treatment: preliminary evidence of reductions in drinking.

BACKGROUND: Alcohol use disorder (AUD) treatment remains greatly underutilized. Innovative strategies are needed to improve AUD treatment access and patient engagement. The Ria Treatment Platform (RTP) is a patient-centered telemedicine AUD treatment program accessed through a smartphone application (app) that includes a package of physician visits (with AUD prescriptions as appropriate), text- and phone-based support from a recovery coach, video monitoring of medication adherence, and Bluetooth-linked breathalyzer tracking of alcohol intake. OBJECTIVES: The purpose of the current study is to examine changes in alcohol use among patients utilizing the RTP. METHODS: This study examines daily breathalyzer blood alcohol content (BAC) readings collected from 77 adult patients (50.7% male) over the first 90 days in treatment with the RTP. Data were analyzed using dynamic structural equation modeling. RESULTS: The treatment retention rate at 90 days was 55%. The best fit for the BAC data was given by a cubic curve, which showed that among patients who remained engaged for 90 days average BAC levels declined approximately 50% (from .091 to .045) from baseline to day 90. CONCLUSION: This study provides preliminary evidence of substantial alcohol use reductions among patients utilizing the RTP, an innovative telemedicine program accessed via smartphone. Although other alcohol-reduction apps have shown promise from scientific evaluations, the RTP appears to be the only app that incorporates physician-prescribed medication and a recovery coach. Research incorporating random assignment and meaningful comparison groups is needed to further evaluate this promising strategy.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

A method to quantify illicit intake of drugs from urine: methamphetamine.

Qualitative urinalysis can verify abstinence of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such as methamphetamine (MA), a single episode of abuse can result in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug use but do not achieve almost complete abstinence are classified as ineffective. Using nonpharmacologic doses of deuterium-labeled l-methamphetamine (l-MA-d(3)) we have developed a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of l-MA-d(3) daily and challenged with 15, 30, and 45 mg of nonlabeled d-MA (d-MA-d(0)) after reaching plasma steady status of l-MA-d(3). Urinary concentration ratios of d-MA-d(0) to l-MA-d(3) provided clear separation of the administered doses with as little as 15-mg dose increments. Administered doses could not be resolved using d-MA-d(0) concentrations alone. In conclusion, the urinary [d-MA-d(0)]:[l-MA-d(3)] provides a quantitative, continuous measure of illicit MA exposure. The method reliably detects small, clinically relevant changes in illicit MA intake from random urine specimens, is amenable to deployment in clinical trials, and can be used to quantify patterns of MA abuse.

Characterizing methamphetamine withdrawal in recently abstinent methamphetamine users: a pilot field study.

BACKGROUND: Methamphetamine dependence has become a significant problem, but methamphetamine withdrawal symptoms have not been well studied. METHODS: This prospective observational pilot study was designed to examine withdrawal symptoms, mood, anxiety, cognitive function, and subjective measures of sleep over a 4-week period in six patients entering residential treatment for methamphetamine dependence. RESULTS: Methamphetamine withdrawal symptoms, mood, and anxiety symptoms all resolve fairly quickly within 2 weeks of cessation of methamphetamine. Sleep was disrupted over the course of the 4-week study. No clinically significant alterations in blood pressure or heart rate were identified. This study did not demonstrate any alterations in cognitive function over the 4 weeks of the residential stay. CONCLUSIONS: This pilot study points toward the need for a double-blind, placebo-controlled amphetamine withdrawal paradigm in humans where changes in sleep, cognitive function, and withdrawal measures can be explored more fully. SCIENTIFIC SIGNIFICANCE: This study extends the literature by pointing toward a methamphetamine withdrawal syndrome that includes alterations in measures of sleep quality and refreshed sleep, early improvement in depression and anxiety symptoms, most striking during the first week, but persisting into the second week.

Validation of triage criteria for deciding which apparently inebriated persons require emergency department care.

OBJECTIVES: The sensitivity and specificity of consensus triage criteria for identifying which apparently inebriated patients could be triaged to care in a sobering centre were determined. Sensitivity and specificity for modifications to these criteria were also investigated. METHODS: Paramedics prospectively collected data on apparently inebriated persons en route to the emergency department (ED). 99 of these patients' ED charts were retrospectively reviewed to assess who actually required ED care. RESULTS: Of 99 subjects with both paramedic and ED chart data available, most were male (89%), homeless (57%) and found on the street (81%). Five were admitted and 13 others appeared to require ED care. Per consensus criteria, only 40 were eligible for triage to a sobering centre, but among those were five who appeared to require ED care (sensitivity 72%, 95% CI 47% to 90%; specificity 43%, 95% CI 32% to 55%). Paramedic opinion alone was specific (80%) but not very sensitive (39%). Lowering the pulse exclusion threshold from 130 to 83 would increase sensitivity to 100%, but decrease specificity to 22%. A simple post hoc rule excluding those with age >55 or pulse >83 from non-ED care had high sensitivity (94%) and fair specificity (61%). The consensus criteria's sensitivity and specificity varied (65-83% and 44-49%, respectively) depending on which ED services were considered optional (eg, psychiatric consultation, ECG, intravenous fluids, etc.). CONCLUSION: Most apparently inebriated individuals in this study did not require ED care, but prospective identification of these persons is difficult. A low exclusion cut-off for tachycardia may improve sensitivity.

Stereoselectivity in the human metabolism of methamphetamine.

AIM: To characterize the formation and urinary elimination of metabolites of S-(+) and R-(-) methamphetamine (MA) in humans. METHODS: In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg(-1), R-(-)-MA 0.25 and 0.5 mg kg(-1), racemic MA 0.5 mg kg(-1), or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS: An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(-)-AMP (P < 0.001). Furthermore, less R-(-)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P= 0.02). Correspondingly, S-(+)-MA excretion was less than R-(-)-MA (42% vs. 52%; P= 0.005). CONCLUSIONS: The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8-11%) than AMP (2-7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism.

Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled R-methamphetamine: selection of the R-methamphetamine dose.

All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), we have developed a method to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from our study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction.

An examination of drug craving over time in abstinent methamphetamine users.

Craving for addictive drugs may predict relapse in abstinent addicts. To assess relationships between craving and use, we examined changes in craving for methamphetamine (MA) in a sample of 865 outpatients in a multisite 16-week MA-treatment study. Craving was assessed on a 0-100 scale, and MA use was assessed by self-report and confirmed by urinalysis. We hypothesized that the magnitude of craving would decline (decay) with increased time of abstinence, and that decay would be greater for more frequent MA users, and greater for intravenous (IV) users and smokers as compared to those who used MA intranasally. Craving declined significantly as the number of weeks of consecutive abstinence increased. Rate of decay was greater for IV users and smokers as compared to both intranasal users and oral users, but not for more frequent users of MA. Rate of decay was independent of age, gender, and race/ethnicity. The trajectory to 0 (no) craving was 1 week shorter for females than males because females had significantly lower pretreatment craving scores compared to males. This study confirms that the sooner MA-dependent people are able to quit using and the longer that they are able to stay abstinent, the more likely it is that their craving for MA will decrease over time.

A phase 1 trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion.

BACKGROUND: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. METHODS: Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. RESULTS: Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. CONCLUSION: No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.

Effects of the Psychedelic Amphetamine MDA (3,4-Methylenedioxyamphetamine) in Healthy Volunteers.

Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA, "molly", "ecstasy") appear to have unusual, potentially therapeutic, emotional effects. Understanding their mechanisms can benefit from clinical experiments with related drugs. Yet the first known drug with such properties, 3,4-Methylenedioxyamphetamine (MDA), remains poorly studied and its pharmacokinetics in humans are unknown. We conducted a within-subjects, double-blind, placebo-controlled study of 1.4 mg/kg oral racemic MDA and compared results to those from our prior similar studies with 1.5 mg/kg oral racemic MDMA. MDA was well-tolerated by participants. MDA induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA. MDA self-report effects shared features with MDMA as well as with classical psychedelics. MDA self-report effects lasted longer than those of MDMA, with MDA effects remaining elevated at 8 h while MDMA effects resolved by 6 h. Cmax and AUC0-∞ for MDA were 229 ± 39 (mean ± SD) and 3636 ± 958 µg/L for MDA and 92 ± 61 and 1544 ± 741 µg/L for the metabolite 4-hydroxy-3-methoxyamphetamine (HMA). There was considerable between-subject variation in MDA/HMA ratios. The similarity of MDA and MDMA pharmacokinetics suggests that the greater duration of MDA effects is due to pharmacodynamics rather than pharmacokinetics.

The clinical pharmacology of intranasal l-methamphetamine.

BACKGROUND: We studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant. METHODS: 12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured. RESULTS: Plasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen. CONCLUSION: Inhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.

Addiction to prescription opioids: characteristics of the emerging epidemic and treatment with buprenorphine.

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opioids and the fear of producing addiction in some patients. In this article, the authors characterize the emerging epidemic of prescription opioid abuse, discuss the utility of buprenorphine in the treatment of addiction to prescription opioids, and present illustrative case histories of successful treatment with buprenorphine.

A nine session manual of motivational enhancement therapy for methamphetamine dependence: adherence and efficacy.

Motivational enhancement therapy (MET) is a brief therapy shown to be effective for problem drinkers. Because the response to MET for other addictive disorders is mixed, we assessed the utility of increasing the number of sessions in subjects with methamphetamine (MA) dependence. One therapist was trained in a nine-session manual of MET, which was tested over eight weeks in 30 MA-dependent outpatients. Adherence to the manual was assessed by two raters, who reviewed a random sample of 15 audiotaped therapy sessions. Interventions were rated on a seven-point Likert scale for frequency/extensiveness (1 = not at all to 7 = extensively) and skill level (1 = unacceptable to 7 = high level of mastery). Ratings of adherence were moderate for frequency/extensiveness (4.2 +/- 2.2 and 4.3 +/- 1.8; Mean +/- SD) and high for skill level (5.4 +/- 0.6 and 5.2 +/- 0.4). Subjects attended 7.0 +/- 2.5 (78%) of nine sessions. Self-reported days of methamphetamine use decreased from 841/1793 (47%) of the 60 days prior to study entry to 448/1458 (31%) during the study (p = 0.011). MA-positive urine samples decreased from 76/118 (64%) during screening to 93/210 (44%) during treatment (p = 0.015). The MET manual was readily learned, and subjects attended a high proportion of therapy sessions with marked reductions in methamphetamine use.

Human pharmacology of the methamphetamine stereoisomers.

OBJECTIVE: To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers. METHODS: In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for "intoxication," "good drug effect," and "drug liking") were obtained. RESULTS: Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3-15.0 hours) than for d-methamphetamine (10.2-10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 +/- 23.4 beats/min, 13.5 +/- 18.5 beats/min, and 10.7 +/- 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 +/- 17.8 beats/min and 34.5 +/- 18.9 beats/min, respectively, versus 19.5 +/- 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 +/- 35.3 versus 30.3 +/- 24.9) and drug liking (47.7 +/- 35.1 versus 28.6 +/- 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures. CONCLUSION: The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities.

Development and Testing of a Smartphone-Based Cognitive/Neuropsychological Evaluation System for Substance Abusers.

INTRODUCTION: In methamphetamine (MA) users, drug-induced neurocognitive deficits may help to determine treatment, monitor adherence, and predict relapse. To measure these relationships, we developed an iPhone app (Neurophone) to compare lab and field performance of N-Back, Stop Signal, and Stroop tasks that are sensitive to MA-induced deficits. METHODS: Twenty healthy controls and 16 MA-dependent participants performed the tasks in-lab using a validated computerized platform and the Neurophone before taking the latter home and performing the tasks twice daily for two weeks. RESULTS: N-Back task: there were no clear differences in performance between computer-based vs. phone-based in-lab tests and phone-based in-lab vs. phone-based in-field tests. Stop-Signal task: difference in parameters prevented comparison of computer-based and phone-based versions. There was significant difference in phone performance between field and lab. Stroop task: response time measured by the speech recognition engine lacked precision to yield quantifiable results. There was no learning effect over time. On an average, each participant completed 84.3% of the in-field NBack tasks and 90.4% of the in-field Stop Signal tasks (MA-dependent participants: 74.8% and 84.3%; healthy controls: 91.4% and 95.0%, respectively). Participants rated Neurophone easy to use. CONCLUSION: Cognitive tasks performed in-field using Neurophone have the potential to yield results comparable to those obtained in a laboratory setting. Tasks need to be modified for use as the app's voice recognition system is not yet adequate for timed tests.

MDMA Impairs Response to Water Intake in Healthy Volunteers.

Hyponatremia is a serious complication of 3,4-methylenedioxymethamphetamine (MDMA) use. We investigated potential mechanisms in two double-blind, placebo-controlled studies. In Study 1, healthy drug-experienced volunteers received MDMA or placebo alone and in combination with the alpha-1 adrenergic inverse agonist prazosin, used as a positive control to release antidiuretic hormone (ADH). In Study 2, volunteers received MDMA or placebo followed by standardized water intake. MDMA lowered serum sodium but did not increase ADH or copeptin, although the control prazosin did increase ADH. Water loading reduced serum sodium more after MDMA than after placebo. There was a trend for women to have lower baseline serum sodium than men, but there were no significant interactions with drug condition. Combining studies, MDMA potentiated the ability of water to lower serum sodium. Thus, hyponatremia appears to be a significant risk when hypotonic fluids are consumed during MDMA use. Clinical trials and events where MDMA use is common should anticipate and mitigate this risk.

Effects of 3,4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting.

The drug 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy", "molly") is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a small (n=12) within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e. increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e. decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class.

Repeated psychological stress testing in stimulant-dependent patients.

Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine- or methamphetamine-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. Cocaine users and methamphetamine users did not respond similarly in their craving responses. Reported craving for methamphetamine after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response.