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.

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.

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.

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.

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.

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.

Impact of prospectively determined A118G polymorphism on treatment response to injectable naltrexone among methamphetamine-dependent patients: an open-label, pilot study.

OBJECTIVES: Methamphetamine (MA) addiction has no known effective pharmacotherapy. Small trials showed beneficial effects for oral naltrexone in amphetamine users. Trials in alcohol-dependent subjects showed better response in persons with the A118G single nucleotide polymorphism of the µ-opioid receptor. We conducted a pharmacogenetic trial of sustained release intramuscular naltrexone to examine the role of the A118G single nucleotide polymorphism in MA dependence. METHOD: All eligible A118G subjects screened were enrolled; an equal number of wild type (A118A) subjects were selected using modified urn randomization, balanced on sex and frequency of recent MA use. Enrolled subjects received a single 380 mg naltrexone injection and weekly psychotherapy for 4 weeks. Self-report of MA use and urine toxicology for MA was assessed twice weekly. Urine samples with less than 1000 ng/mL of MA were considered negative. RESULTS: Eleven A118G and 11 A118A subjects were enrolled. There were no significant differences between the groups in days of abstinence from MA use (11.5 vs 14.8, respectively, P = 0.51), the number of MA-negative urine samples (1.7 vs 1.8, respectively, P = 0.97), consecutive MA-negative urine samples (1.0 vs 1.5, respectively, P = 0.91), or the number of MA-negative urine samples before first relapse (0.9 vs 1.5, respectively, P = 0.86). CONCLUSIONS: Although A118G polymorphism has been shown to be associated with improved treatment response to naltrexone among alcoholics, whether this polymorphism impacts naltrexone treatment response among MA users is unclear at this time.

MDMA effects consistent across laboratories.

RATIONALE: Several laboratories have conducted placebo-controlled drug challenge studies with 3,4-methylenedioxymethamphetamine (MDMA), providing a unique source of data to examine the reliability of the acute effects of the drug across subject samples and settings. We examined the subjective and physiological responses to the drug across three different laboratories and investigated the influence of prior MDMA use. METHODS: Overall, 220 healthy volunteers with varying levels of previous MDMA experience participated in laboratory-based studies in which they received placebo or MDMA orally (1.5 mg/kg or 125-mg fixed dose) under double-blind conditions. Cardiovascular and subjective effects were assessed before and repeatedly after drug administration. The studies were conducted independently by investigators in Basel, San Francisco, and Chicago. RESULTS: Despite methodological differences between the studies and differences in the subjects' drug use histories, MDMA produced very similar cardiovascular and subjective effects across the sites. The participants' prior use of MDMA was inversely related to feeling "Any Drug Effect" only at sites testing more experienced users. CONCLUSIONS: These data indicate that the pharmacological effects of MDMA are robust and highly reproducible across settings. There was also modest evidence for tolerance to the effects of MDMA in regular users.

Developing biomarkers for methamphetamine addiction.

There are an estimated 11.7 million methamphetamine (MA) abusers in the United States and epidemics of MA addiction are occurring worldwide. In our human laboratory and outpatient clinical trials we use innovative methods to quantify the severity of MA addiction and test biomarkers that may predict response to therapy or risk of relapse. One potential biomarker of addiction is the quantity of abused drug intake. Qualitative urinalysis is used in clinical trials and during treatment but provides only a binary outcome measure of abuse. Using non-pharmacologic doses of deuterium labeled l-MA we have developed a continuous quantitative measure to estimate the bioavailable amount of MA addicts ingest. Brain Derived Neurotrophic Factor is a neurotrophin that encourages growth and differentiation of new neurons and synapses. Low BDNF levels are seen in many addictive disorders and BDNF is elevated in recovering MA addicts, suggesting BDNF may be a marker of MA addiction. We are investigating the effects of controlled doses of MA on BDNF levels and gene regulation and measuring BDNF in our clinical trials. We believe both patients and clinical researches will benefit from the addition of new, objective and quantifiable outcome measures that reflect disease severity and recovery from addiction.

A simple, novel method for assessing medication adherence: capsule photographs taken with cellular telephones.

OBJECTIVES: Medication nonadherence is an important factor in clinical practice and research methodology. Although many methods of measuring adherence have been investigated, there is as yet no "gold standard." We compared the usefulness and accuracy of a novel measure of adherence, photographs taken by cellular telephones with 2 incumbents: capsule count and the Medication Event Monitoring System (MEMS). METHOD: Twenty subjects participated in a clinical trial of the efficacy of modafinil for the treatment of methamphetamine dependence. Subjects were issued cell phones and medication in MEMS Cap equipped bottles and were instructed to take 1 capsule a day for 8 weeks, recording adherence with both systems. Pill counts were recorded at weekly inpatient visits. Subjects were paid for participation and for each capsule photograph and the returned medication bottle with MEMS Cap. RESULTS: Capsule count-indicated adherence (proportion of prescribed medication taken) was 94.9%. When compared with capsule count, the novel method was found to underestimate adherence, whereas MEMS overestimated adherence. By using the dosing time data collected, we determined that subjects who dosed at a consistent time daily were more likely to adhere to the prescribed regimen. We also detected discrepancies in the timestamps recorded by MEMS. CONCLUSIONS: Capsule photographs are a useful measure of adherence, allowing more accurate time measures and more frequent adherence assessment than MEMS or capsule count. Given the ubiquity of cellular telephone use, and the relative ease of this adherence measurement method, we believe it is a useful and cost-effective approach.

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.

Cocaethylene formation following ethanol and cocaine administration by different routes.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d5) was administered in all conditions. Oral cocaine-d5 2.0 mg/kg, intravenous cocaine-d5 1.0 mg/kg, and smoked cocaine-d5 (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d3) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d5, cocaethylene-d5, cocaethylene-d3, and benzoylecgonine-d5 were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.

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.

Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: a placebo-controlled trial.

RATIONALE: Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. OBJECTIVES: The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. METHODS: Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. RESULTS: No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported "typical" effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). CONCLUSIONS: Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

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.

Investigating the mechanisms of hallucinogen-induced visions using 3,4-methylenedioxyamphetamine (MDA): a randomized controlled trial in humans.

BACKGROUND: The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition. CONCLUSIONS/SIGNIFICANCE: Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception. TRIAL REGISTRATION: Clinicaltrials.gov NCT00823407.

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.