Faculty Bibliography

BACKGROUND/UNASSIGNED:Sub-anesthetic ketamine administration may be helpful for substance use disorders. Converging evidence suggests that the efficacy of ketamine for certain conditions may implicate a subset of its psychoactive effects. AIMS/UNASSIGNED:The aim of this analysis is to evaluate whether the mystical-type effects of ketamine are critical for clinical efficacy in alcohol-dependent individuals. In this secondary analysis, we determine if a subset of the psychoactive effects of ketamine, the so-called mystical-type experience, mediates the effect of ketamine, when combined with motivational enhancement therapy, on at-risk drinking behavior in alcohol-dependent individuals interested in treatment. METHODS/UNASSIGNED:Forty alcohol dependent adults were randomized to either a 52-minute infusion of ketamine or midazolam, which they received on a designated quit-day during the second week of a five-week motivational enhancement therapy regimen. Psychoactive effects were assessed following the infusion, and alcohol use was monitored for the subsequent 3 weeks at each twice-weekly visit. RESULTS/UNASSIGNED:We found that ketamine leads to significantly greater mystical-type effects (by Hood Mysticism Scale) and dissociation (by Clinician Administered Dissociative States Scale) compared to the active control. Ketamine also led to significant reduction in at-risk drinking. The Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior. CONCLUSIONS/UNASSIGNED:This trial adds evidence to the literature on the importance of mystical-type experiences in addiction treatment. Future research should continue to investigate the relationship between the psychoactive effects of psychedelic therapeutics and clinical outcomes for other substance use and mental health disorders.

BACKGROUND:Sub-anesthetic ketamine infusions may benefit a range of psychiatric conditions, including alcohol and cocaine use disorders. Currently, there are no effective pharmacological treatments for cannabis use disorder. OBJECTIVES/OBJECTIVE:The objective of this uncontrolled proof of concept trial was to test the feasibility, tolerability, and potential therapeutic effects of integrating ketamine infusions with a behavioral platform of motivational enhancement therapy and mindfulness-based relapse prevention in treating cannabis use disorder (CUD). METHODS:Eight cannabis-dependent individuals (four female, four male) receiving motivational enhancement therapy and mindfulness-based relapse prevention behavioral treatments completed this single-blind outpatient 6-week study. Participants received either one or two infusions of ketamine (0.71 mg/kg [infusion 1]; 1.41 mg/kg [infusion 2] for non-responders) during the study. Participants self-reported cannabis use (Timeline Follow-Back) and underwent an assessment of confidence in abstaining from using cannabis (Drug-Taking Confidence Questionnaire) at predetermined time points throughout the study. RESULTS:Ketamine infusions were well-tolerated and there were no adverse events. Frequency of cannabis use decreased significantly from baseline (B = 5.1, s.e = 0.7) to the week following the first infusion (B = 0.8, s.e = 0.412), and remained reduced at the end of the study (B = 0.5, s.e = 0.3). Participants' confidence in their ability to abstain from cannabis in potentially triggering situations increased significantly from baseline to the end of study. CONCLUSIONS:These findings suggest that combining ketamine with behavioral therapy is feasible,tolerable, and potentially helpful, in treating cannabis-dependent individuals.

OBJECTIVE/UNASSIGNED:Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes. METHODS/UNASSIGNED:Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion. RESULTS/UNASSIGNED:Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events. CONCLUSIONS/UNASSIGNED:A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.

BACKGROUND:Cocaine use disorder (CUD) remains a substantial public health problem with no clearly effective pharmacotherapy available. In a prior trial, combined amphetamine and topiramate treatment significantly reduced cocaine use among individuals demonstrating the most frequent use at baseline. This trial targeted such frequent users. METHODS:A double-blind, randomized placebo-controlled trial, testing the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo over a 12-week medication phase was conducted. The two-site outpatient trial included 127 adults (96 males) with CUD using at least 9 days in the prior month. MAS-ER was titrated to a maximum dose of 60 mg/day and topiramate to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved three consecutive abstinent weeks at the end of the study (EOS) as measured by urine toxicology and self-report. RESULTS:The proportion of participants achieving three abstinent weeks at the EOS was significantly (P = .03) larger in the treatment (14.1%) compared to the placebo group (0.0%), while controlling for baseline cocaine use, sex, current alcohol use disorder, and site. Of note, due to conservative cardiac safety-parameters a considerable number of individuals in the treatment group were discontinued from study medication (20.3%). CONCLUSIONS:While these findings provide further evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in CUD adults with frequent use it remains possible that the combination treatment is no more effective than either treatment alone. Despite this, the study provides a valuable "proof of concept."

Background: Currently, there are no established pharmacotherapies for cannabis use disorders (CUDs). As a long-acting alpha-2-adrenergic receptor agonist, guanfacine extended-release (G-XR) could be useful in the treatment of CUDs by mitigating withdrawal and improving behavioral control. Objectives: To evaluate the feasibility and tolerability of G-XR as a treatment for CUDs. Methods: In an eight-week open-label outpatient pilot trial, we evaluated the safety and tolerability of G-XR in 22 cannabis dependent individuals. Using 2 different titration schedules, G-XR was gradually titrated to a dose of 4 mg or the highest dose tolerated. All participants received standard medication management. Results: Retention at week eight was 41%. Average daily amount of cannabis use (in grams: F_1,86 = 8.74, p = .004; in dollars: F_1,86 = 16.67, p < .0001) and cannabis using days (F_1,86 = 7.67, p = .007) significantly reduced over the course of study participation. There were no significant differences between the titration schedules on emergence of side effects (Fisher exact test, p = .378) or retention (Log-Rank Test X²₁ = 0.021, p = .886). A total of 3 participants achieved 3 weeks or greater of total abstinence. Conclusions: G-XR is a feasible treatment for CUDs, and should be evaluated further in an efficacy trial.

OBJECTIVE/UNASSIGNED:Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. METHODS/UNASSIGNED:Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). RESULTS/UNASSIGNED:Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. CONCLUSIONS/UNASSIGNED:A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

STUDY DESIGN:Retrospective review. OBJECTIVES:To identify factors associated with successful outcomes in patients treated with vertebral body stapling (VBS) for idiopathic scoliosis. SUMMARY OF BACKGROUND DATA:The standard of care for moderate scoliosis (20°-45°) consists of observation and bracing with the goal of halting curve progression. Although several recent studies have confirmed the efficacy of bracing in altering the natural history of scoliosis, bracing is not universally effective. Recent studies have demonstrated that VBS is a safe and viable treatment for some young patients with scoliosis at risk for progression. The identification of factors associated with successful outcomes in VBS for idiopathic scoliosis would better define the population likely to benefit from VBS. METHODS:We retrospectively reviewed all patients from a single institution treated with VBS who met previously defined inclusion criteria. Successful treatment was defined as avoidance of a fusion and a final Cobb angle no more than 10° greater than the pretreatment Cobb angle. RESULTS:We identified 63 patients who met inclusion criteria. The patients underwent VBS at a mean age of 10.78 years and had a mean follow-up of 3.62 years (minimum 2 years). The mean pre-op Cobb angle for stapled thoracic curves was 29.5°. Seventy-four percent of the patients who had VBS of the thoracic curve have avoided progression and/or fusion, and the mean Cobb angle at most recent follow-up was 21.8°. The mean preoperative Cobb angle for lumbar curves was 31.1°. Eighty-two percent of the patients who had VBS of the lumbar curve have avoided progression and/or fusion, and their mean Cobb angle at follow-up was 21.6°. CONCLUSION:VBS is effective at preventing progression and fusion for moderate idiopathic scoliosis in immature patients. The complication rates are low.

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.

A promising approach to addressing substance use disorders is to integrate pharmacotherapy with a behavioral treatment with which synergy is possible. In this review, we focus on recent research suggesting that this approach may be effective for cocaine and cannabis use disorders, both of which currently lack efficacious medications. We summarize potential targets of pharmacotherapy of particular relevance to combined medication-behavioral treatment and examine preliminary evidence of clinical efficacy. Common to these promising medications is a hypothesized mechanism of action predicated on reversing drug-related neural adaptations, such as high reactivity to stress or drug cues, that might undermine fruitful engagement with behavioral treatment. We also review emerging medications, such as certain glutamatergic and serotonergic agents, which may be feasibly integrated with existing treatments. We conclude with an outline of future directions for research.