Faculty Bibliography

Importance/UNASSIGNED:Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. Objective/UNASSIGNED:To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. Design, Setting, and Participants/UNASSIGNED:In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Interventions/UNASSIGNED:Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. Main Outcomes and Measures/UNASSIGNED:The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. Results/UNASSIGNED:A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 5 (5.3%) were Black, 16 (16.8%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Conclusions and Relevance/UNASSIGNED:Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02061293.

BACKGROUND:Overdose education and naloxone distribution (OEND) trains people who use opioids (PWUO) in how to intervene in cases of opioid overdose but best practices have not been assessed empirically. METHODS:PWUO along with a significant other (SO) were randomized to one of three training conditions. In the Treatment-as-Usual (TAU) condition, participants were randomized to receive minimal overdose-related education. In the extended training (ET) condition, PWUO received an extended training, while their SO received no overdose training. In the final condition, both the participant and SO received the extended overdose training (ETwSO). Outcome measures were naloxone use and overdose knowledge and competency assessed immediately before and after training, and at 1-, 3-, 6-, and 12-month timepoints following training. RESULTS:Three hundred and twenty-one PWUO (w/ a SO) were randomized. All intensities of OD training were associated with sustained increases in OD knowledge/ competency (versus pre-training baseline p's < 0.01). PWUO intervened in 166 ODs. The 12-month incidence of naloxone use did not significantly differ between groups. Extended training (ET + ETwSO) compared to TAU resulted in significantly greater naloxone utilization by: 30 days (10.1% vs 4.1%, p = 0.041), 60 days (16.4% vs 5.2%, p<0.001) and 90 days (17.9% vs 9.5%, p = 0.039). CONCLUSIONS:All intensities of OD training were associated with sustained increases in OD knowledge and competency, and equivalent rates of successful naloxone use. More extensive training increased naloxone utilization during the first 3 months. However, the benefits of more comprehensive training should be balanced against feasibility.

Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.

BACKGROUND:Despite the existence of effective pharmacotherapies, rates of opioid use disorder and opioid overdose deaths have continued to increase. Emergency department (ED) visits provide an important opportunity to engage in treatment patients with untreated opioid use disorder (OUD). Case management implemented in other settings is effective in linking those with opioid and other drug use disorders to longer-term treatment, but research has not established its efficacy in the ED. Here we report the results of a trial of Strengths-Based Case Management (SBCM) for people with untreated OUD who are identified during ED visits, with the primary goal of linking them to pharmacologic treatment. METHODS:The study identified patients with untreated OUD during a treatment episode at a large urban ED. The study randomly assigned three hundred participants in 1:1 ratio to receive SBCM or screening, assessment, and referral (SAR) to OUD treatment. Those assigned to SBCM received up to six sessions of SBCM with the primary goal of linkage to treatment. Primary outcomes were initiation of treatment and engagement in pharmacotherapy for OUD. The study defined a "successful outcome" for opioid use as a 3-month urine negative for illicit opioids and no more than 2 days of self-reported opioid misuse in the 4 weeks prior to the 3-month interview. RESULTS:Rates of treatment initiation were not significantly different in the SBCM and SAR groups (57.4% vs. 49.7%, respectively, p > 0.05), nor did engagement in pharmacotherapy differ significantly between groups (p > 0.05). During the 90 days following the index ED visit, SBCM and SAR participants engaged in pharmacotherapy for a mean of 21.8% (SD = 35.1%) versus 17.7% (SD = 31.0%) of days, respectively. Likewise, no significant difference occurred between groups in rates of "successful opioid use outcome" as defined a priori (p > 0.05), although self-reported opioid use over the entire 6-month follow-up period was lower in the SBCM group (10.8 vs. 13.4 days/month, p = 0.042). CONCLUSIONS:SBCM-ED did not improve OUD treatment initiation and engagement in this ED study. Although these findings do not necessarily generalize to all EDs, other approaches, such as direct referral or initiation of treatment in the ED, have considerable empirical support, and should be implemented where they are feasible.

AIMS/OBJECTIVE:To investigate among older adults with DSM-5 alcohol use disorder (AUD) the relevance of (1) baseline DSM-5 AUD severity, (2) age of DSM-5 AUD onset, and (3) the interactions of DSM-5 AUD severity*treatment condition and age of DSM-5 AUD onset*treatment condition for the prediction of AUD treatment outcomes. METHODS:The international multicenter RCT "ELDERLY-Study" compared outpatient motivational enhancement therapy (4 sessions) with outpatient motivational enhancement therapy followed by community reinforcement approach for seniors (8 sessions) in adults aged 60+ with DSM-5 AUD. Baseline and 1-, 3-, and 6-month follow-up data from the German and Danish ELDERLY-sites (n = 544) were used (6-month participation rate: 75.9%). DSM-5 AUD diagnoses were obtained using the Mini International Neuropsychiatric Interview and alcohol use using Form 90. Associations between DSM-5 AUD severity and age of onset and AUD treatment outcomes were investigated using multiple logistic regression and generalized linear models. RESULTS:The sample was diverse in AUD severity (severe: 54.9%, moderate: 28.2%, mild: 16.9%) and age of onset (median: 50 years; 12-78 years). Overall, with few exceptions, neither AUD severity, nor age of onset, nor their respective interactions with treatment condition significantly predicted drinking outcomes at the different follow-ups (P ≥ 0.05). CONCLUSIONS:No indication was found for the need to tailor treatment content according to DSM-5 AUD severity and earlier onset in older adults.

Recent resting-state functional MRI studies in stroke patients have identified two robust biomarkers of acute brain dysfunction: a reduction of inter-hemispheric functional connectivity between homotopic regions of the same network, and an abnormal increase of ipsi-lesional functional connectivity between task-negative and task-positive resting-state networks. Whole-brain computational modelling studies, at the individual subject level, using undirected effective connectivity derived from empirically measured functional connectivity, have shown a reduction of measures of integration and segregation in stroke as compared to healthy brains. Here we employ a novel method, first, to infer whole-brain directional effective connectivity from zero-lagged and lagged covariance matrices, then, to compare it to empirically measured functional connectivity for predicting stroke versus healthy status, and patient performance (zero, one, multiple deficits) across neuropsychological tests. We also investigated the accuracy of functional connectivity versus model effective connectivity in predicting the long-term outcome from acute measures. Both functional and effective connectivity predicted healthy from stroke individuals significantly better than the chance-level; however, accuracy for the effective connectivity was significantly higher than for functional connectivity at 1- to 2-week, 3-month and 1-year post-stroke. Predictive functional connections mainly included those reported in previous studies (within-network inter-hemispheric and between task-positive and -negative networks intra-hemispherically). Predictive effective connections included additional between-network links. Effective connectivity was a better predictor than functional connectivity of the number of behavioural domains in which patients suffered deficits, both at 2-week and 1-year post-onset of stroke. Interestingly, patient deficits at 1-year time-point were better predicted by effective connectivity values at 2 weeks rather than at 1-year time-point. Our results thus demonstrate that the second-order statistics of functional MRI resting-state activity at an early stage of stroke, derived from a whole-brain effective connectivity, estimated in a model fitted to reproduce the propagation of neuronal activity, has pertinent information for clinical prognosis.

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.