Elias Dakwar

The Effects of Subanesthetic Ketamine Infusions on Motivation to Quit and Cue-Induced Craving in Cocaine-Dependent Research Volunteers

BACKGROUND Cocaine dependence involves problematic neuroadaptations that might be responsive to modulation of glutamatergic circuits. This investigation examined the effects of subanesthetic ketamine infusions on motivation for quitting cocaine and on cue-induced craving in cocaine-dependent participants, 24 hours postinfusion. METHODS Eight volunteers with active DSM-IV cocaine dependence not seeking treatment or abstinence were entered into this crossover, double-blind trial. Three 52-min intravenous infusions were administered: ketamine (.41 mg/kg or .71 mg/kg) or lorazepam 2 mg, counterbalanced into three orderings in which ketamine .41 mg/kg always preceded the .71 mg/kg dose. Infusions were separated by 48 hours, and assessments occurred at baseline and at 24 hours postinfusion. Outcomes were change between postinfusion and preinfusion values for: 1) motivation to quit cocaine scores with the University of Rhode Island Change Assessment; and 2) sums of visual analogue scale craving ratings administered during cue exposure. RESULTS Compared with the active control lorazepam, a single ketamine infusion (.41 mg/kg) led to a mean 3.9-point gain in University of Rhode Island Change Assessment (p = .012), which corresponds to an approximately 60% increase over preceding values. There was a reduction of comparable magnitude in cue-induced craving (p = .012). A subsequent ketamine infusion (.71 mg/kg) led to further reductions in cue-induced craving compared with the control. Infusions were well-tolerated. CONCLUSIONS Subanesthetic ketamine demonstrated promising effects on motivation to quit cocaine and on cue-induced craving, 24 hours postinfusion. Research is needed to expand on these preliminary results and to evaluate the efficacy of this intervention in clinical settings.

Mindfulness impairments in individuals seeking treatment for substance use disorders

Background: Mindfulness training may be an effective treatment for substance use disorders (SUDs). Little research has been done, however, on baseline levels of mindfulness in the substance using population. Objectives/Methods: We investigated mindfulness levels using the Mindful Attention Awareness Scale (MAAS) in individuals presenting for substance use treatment, and compared polydrug vs. monodrug users, as well as investigated for differences between groups based on substance used, predicting that group means would fall below the mean obtained from a large national adult sample, that the different drug groups would have comparable scores, and that the polydrug users would have a significantly lower score than do monodrug users. Results: We found that the means of most drug groups were below the national mean, and that the polydrug users had a lower score on the MAAS than did monodrug users (4 vs. 3.6, p = 0.04). We were also surprised to find that opiate users had a significantly higher score (4.31) than did users of other substances (p = 0.02). Conclusion/Significance: These results suggest that mindfulness deficits may be common in the substance using population, that there may be sub-groups in which these deficits are more pronounced, and that they may be a suitable focus of SUD treatment. These findings lend support to the ongoing development of mindfulness-based treatments for SUDs, and suggest that particular sub-groups may benefit more than others. Future research can aim at clarifying these deficits, and at elucidating their clinical relevance.

The Utility of Attention-Deficit/Hyperactivity Disorder Screening Instruments in Individuals Seeking Treatment for Substance Use Disorders

OBJECTIVE Several screening tools for attention-deficit/hyperactivity disorder (ADHD) have been validated in non-substance-abusing populations, but limited data are available regarding their utility in adults with current substance use disorders. The aim of this study was to determine the sensitivity, specificity, and positive and negative predictive values of 3 commonly used ADHD screening instruments in cocaine-dependent individuals. METHOD Adults seeking treatment for cocaine dependence (N = 102) were administered 3 self-report instruments between May 2009 and April 2011: the Conners Adult ADHD Rating Scale (CAARS), the Wender Utah Rating Scale (WURS), and the Adult ADHD Self-Report Scale-Version 1.1 (ASRS-V1.1). They then met with masters-level clinicians who administered the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID). With the CAADID serving as the gold standard, the validity of the screening instruments was determined, both singly and in combination. RESULTS Twenty-five (25%) of the 102 patients met DSM-IV criteria for ADHD or ADHD not otherwise specified (NOS) based on the CAADID. Kappa scores determining agreement between the screening tools and the CAADID (with ADHD NOS labeled as ADHD or labeled as not ADHD) ranged from 0.37 to 0.69. Sensitivity scores for the broadest range of ADHD cases were 80.0%, 87.5%, and 60.9% for the CAARS, WURS, and ASRS-V1.1, respectively. Positive predictive value was highest for the CAARS, at 74.1%, and negative predictive value was highest for the WURS, at 95.1%. The highest sensitivity (96.0%) was found with coadministration of the WURS and CAARS. CONCLUSION While all of the screening instruments were found to have adequate sensitivity and specificity, the CAARS outperformed the other instruments in regard to agreement with the CAADID and positive predictive values. However, the WURS, with the highest sensitivity in regard to the broadest range of ADHD cases, may be the single best instrument for preliminary screening purposes. Further, because the ASRS-V1.1 is the simplest and shortest instrument to administer, it may have advantages when a large number of patients need to be screened.

Therapeutic infusions of ketamine: Do the psychoactive effects matter?

BACKGROUND Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24h postinfusion. METHODS Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions separated by 48h were received: lorazepam (2mg) and two doses of ketamine (0.41mg/kg and 0.71mg/kg, with the former dose always preceding the latter). Infusions were followed within 15min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hoods Mysticism Scale: HMS). At baseline and 24h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure). RESULTS Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71mg/kg was associated with significantly higher HMS scores than was the 0.41mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24h postinfusion. CONCLUSIONS These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.

Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine

OBJECTIVE At present there is no established optimal approach for transitioning opioid-dependent adults to extended-release injection naltrexone (XR-naltrexone) while preventing relapse. The authors conducted a trial examining the efficacy of two methods of outpatient opioid detoxification for induction to XR-naltrexone. METHOD Participants were 150 opioid-dependent adults randomly assigned 2:1 to one of two outpatient detoxification regimens, naltrexone-assisted detoxification or buprenorphine-assisted detoxification, followed by an injection of XR-naltrexone. Naltrexone-assisted detoxification lasted 7 days and included a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications. Buprenorphine-assisted detoxification included a 7-day buprenorphine taper followed by a week-long delay before administration of XR-naltrexone, consistent with official prescribing information for XR-naltrexone. Participants from both groups received behavioral therapy focused on medication adherence and a second dose of XR-naltrexone. RESULTS Compared with participants in the buprenorphine-assisted detoxification condition, participants assigned to naltrexone-assisted detoxification were significantly more likely to be successfully inducted to XR-naltrexone (56.1% compared with 32.7%) and to receive the second injection at week 5 (50.0% compared with 26.9%). Both models adjusted for primary type of opioid use, route of opioid administration, and morphine equivalents at baseline. CONCLUSIONS These results demonstrate the safety, efficacy, and tolerability of low-dose naltrexone, in conjunction with single-day buprenorphine dosing and adjunctive nonopioid medications, for initiating adults with opioid dependence to XR-naltrexone. This strategy offers a promising alternative to the high rates of attrition and relapse currently observed with agonist tapers in both inpatient and outpatient settings.

Exercise and mental illness: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND Regular exercise is thought to be associated with low rates of mental illness, but this association has been inadequately studied. The purpose of this study was to test the hypotheses that the recommended amount of self-reported vigorous exercise would be cross-sectionally associated with reduced prevalence and incidence of various DSM-IV psychiatric disorders, as well as increased rates of remission. METHOD Data were collected from 2001 to 2005 as part of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a 2-wave face-to-face survey conducted by the National Institute on Alcohol Abuse and Alcoholism. For this study, the sample consisted of 23,505 nondisabled adults aged between 18 and 65 years. RESULTS Individuals who engaged in vigorous exercise at Wave 2 were significantly more likely than were nonexercisers to be diagnosed with a current psychiatric disorder (adjusted odds ratio [AOR] = 1.22, 95% CI, 1.12-1.34 for the nationally recommended amount vs no exercise), significantly less likely to attain remission from a psychiatric disorder between waves (AOR = 0.77, 95% CI, 0.65-0.91), and significantly more likely to relapse or be newly diagnosed with a psychiatric disorder between waves (AOR = 1.15, 95% CI, 1.02-1.30). Alcohol dependence and bipolar II disorder were the disorders most strongly associated with exercise. CONCLUSIONS This investigation suggests that the pursuit of vigorous exercise is associated with a vulnerability to mental illness. This surprising finding may be due to reward-related factors that influence both exercise engagement and the expression of certain psychiatric disorders. Prospective trials will be helpful in further clarifying the associations between exercise and mental illness, as the relationships between the 2 are more complex than previously believed.

Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial ☆

BACKGROUND Cannabis use disorder is associated with substantial morbidity and, after alcohol, is the most common drug bringing adolescents and adults into treatment. At present, there are no FDA-approved medications for cannabis use disorder. Combined pharmacologic interventions might be particularly useful in mitigating withdrawal symptoms and promoting abstinence. OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, and lofexidine, an alpha-2 agonist, in treating cannabis dependence. METHODS One hundred fifty six cannabis-dependent adults were enrolled and following a 1-week placebo lead-in phase 122 were randomized in a double-blind, placebo-controlled, 11-week trial. Participants were randomized to receive dronabinol 20mg three times a day and lofexidine 0.6 mg three times a day or placebo. Medications were maintained until the end of week eight, were then tapered over two weeks and patients were monitored off medications during the last study week. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow-back method. RESULTS There was no significant difference between treatment groups in the proportion of participants who achieved 3 weeks of abstinence during the maintenance phase of the trial (27.9% for the medication group and 29.5% for the placebo group), although both groups showed a reduction over time. CONCLUSIONS Based on this treatment study, the combined intervention did not show promise as a treatment for cannabis use disorder.

First Treatment Contact for ADHD: Predictors of and Gender Differences in Treatment Seeking

OBJECTIVES For attention-deficit hyperactivity disorder (ADHD), treatment seeking is a critical first step in treatment initiation and remains insufficiently understood. The aims of this study were to estimate ADHD treatment-seeking probabilities over the lifetime and to identify predictors of treatment seeking for ADHD separately for males and females. METHODS Data were drawn from 2001 to 2005 as part of the National Epidemiologic Survey on Alcohol and Related Conditions, a two-wave face-to-face survey conducted by the National Institute on Alcohol Abuse and Alcoholism (N=34,653). RESULTS The lifetime cumulative probability of ADHD treatment seeking was estimated at 55%. Males identifying as African American, with less than 12 years of education, or paranoid personality disorder or in an older cohort (>30 years old) at the time of interview were more likely to experience delays, whereas males with comorbid alcohol dependence, dysthymic disorder, borderline personality disorder, or histrionic personality disorder were less likely. Among females, older age (>44 years) was the only predictor of a delay to first treatment seeking, whereas bipolar disorder was associated with more rapid treatment seeking. Age of onset had opposite effects on treatment-seeking delays by gender; males but not females with early-onset ADHD were more likely to experience treatment-seeking delays. CONCLUSIONS A large proportion of persons with ADHD do not seek treatment. Furthermore, treatment seeking by males was affected by a greater number of identifiable characteristics, suggesting that males might be more responsive to efforts directed toward expediting treatment entry. Future research should explore how to facilitate early access to treatment for individuals with ADHD.

Naltrexone-Facilitated Buprenorphine Discontinuation: A Feasibility Trial

RATIONALE Buprenorphine is an effective and popular treatment for opioid dependence. It remains unclear, however, when or how to transition stable buprenorphine-maintained individuals to complete abstinence. This trial investigates the feasibility of using naltrexone to facilitate buprenorphine discontinuation in stable individuals who had tolerated a taper to 2mg or less but were unable to terminate entirely due to withdrawal-related distress. METHODS The sample consisted of 6 buprenorphine-maintained individuals in sustained full remission, and who had tolerated a taper but were unable to discontinue altogether. A rapid induction procedure was performed, which included supervised buprenorphine discontinuation, oral naltrexone titration with a starting dose of 6.25mg, and administration of long-acting injectable naltrexone. Participants were followed weekly for 5weeks after the injection, with telephone follow-up occurring at 6months. RESULTS The rapid induction procedure was well tolerated. There was no observed or reported clinical worsening over the course of study participation. Notably, no participants experienced an increase in Subjective Opioid Withdrawal Scale (SOWS) scores after the first oral dose of NTX as compared to day 1 (24hours after last dose of buprenorphine); instead, SOWS scores decreased between days 1 and 7 (p=0.043). All participants were able to discontinue buprenorphine and to remain opioid free during the trial and at follow-up. CONCLUSIONS This preliminary trial represented for all participants the first successful attempt at buprenorphine discontinuation. Further research is needed to better understand if naltrexone is effective at facilitating buprenorphine discontinuation, as well as the feasibility of a sequential approach (buprenorphine stabilization to naltrexone) for opioid use disorders.

Individual mindfulness-based psychotherapy for cannabis or cocaine dependence: a pilot feasibility trial.

BACKGROUND Mindfulness-based approaches may be effective treatments for substance use disorders (SUDs), but they have only been investigated for SUDs in the group setting. METHODS A novel 10-week individual mindfulness-based psychotherapy was provided weekly to participants. Tolerability and therapeutic feasibility were assessed by retention rates, incidence of adverse events or clinical worsening, and abstinence rates at the end of the protocol. RESULTS Twenty-five patients were enrolled overall, and 19 completed (74% overall retention rate). Of the 14 cannabis dependent patients enrolled in the study, 11 completed (79%), and 8 achieved abstinence (57% by intent-to-treat analysis) at 10 weeks. Of the 11 cocaine dependent patients, 8 completed (73%), and 6 achieved abstinence (55% by ITT) at 10 weeks. Abstinence rates were substantially greater than those of historical comparison groups. CONCLUSIONS These findings indicate that mindfulness training can be tolerably and feasibly extended to the individual psychotherapy setting for the treatment of cocaine or cannabis dependence.