Faculty Bibliography

OBJECTIVES/OBJECTIVE:The noradrenergic system plays an important role in the pathophysiology of alcohol use disorder (AUD). Medications in this class may reduce drinking. Our aims were to investigate this in a unique sample of individuals with AUD. METHODS:Thirty-six individuals with AUD were randomized to treatment with prazosin, an alpha-1 noradrenergic antagonist, or placebo, for 6 weeks (target daily dose 16 mg). Hierarchical linear modeling was used to examine the effect of treatment group on rate of change in primary (drinks per week [DPW]) and several secondary outcome measures. RESULTS:Prazosin did not significantly affect rate of reduction in alcohol use in the intent to treat sample (n = 36) compared with placebo, but did significantly increase the rate of reduction in DPW in an optimal treatment exposure subgroup (beta = -0.3; P = 0.01; event rate ratio 0.74; confidence interval 0.59, 0.93; n = 27). Poor adherence and tolerability may have contributed to null effects. Diastolic blood pressure (DBP) moderated the effects of treatment group on rate of reduction in drinks per drinking day, supporting previous work in doxazosin, another alpha-1 antagonist. Specifically, prazosin was associated with greater rates of reduction in drinking compared with placebo in individuals with high but not low DBP. CONCLUSIONS:Our findings do not support the clinical utility of prazosin for all treatment-seeking AUD, but post hoc analyses indicate that it might have some efficacy in individuals who can tolerate it. Further work exploring the clinical utility of DBP as a treatment matching variable, and defining optimal values using sensitivity and specificity analyses, is warranted.

A growing body of evidence shows that existential and spiritual well-being in cancer patients is associated with better medical outcomes, improved quality of life, and serves as a buffer against depression, hopelessness, and desire for hastened death. Historical and recent research suggests a role for psilocybin-assisted psychotherapy in treating cancer-related anxiety and depression. A double-blind controlled trial was performed, where 29 patients with cancer-related anxiety and depression were randomly assigned to treatment with single-dose psilocybin (0.3 mg/kg) or niacin in conjunction with psychotherapy. Previously published results of this trial demonstrated that, in conjunction with psychotherapy, moderate-dose psilocybin produced rapid, robust, and enduring anxiolytic, and anti-depressant effects. Here, we illustrate unique clinical courses described by four participants using quantitative measures of acute and persisting effects of psilocybin, anxiety, depression, quality of life, and spiritual well-being, as well as qualitative interviews, written narratives, and clinician notes. Although the content of each psilocybin-assisted experience was unique to each participant, several thematic similarities and differences across the various sessions stood out. These four participants' personal narratives extended beyond the cancer diagnosis itself, frequently revolving around themes of self-compassion and love, acceptance of death, and memories of past trauma, though the specific details or narrative content differ substantially. The results presented here demonstrate the personalized nature of the subjective experiences elicited through treatment with psilocybin, particularly with respect to the spiritual and/or psychological needs of each patient.

Research on the clinical applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alcohol dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clinical settings, is scarce.Methods:An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alcohol dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qualitative content analysis of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions.Results:Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin.Discussion:The data illuminate change processes in patients' own words during clinical sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clinical sessions, as opposed to interviews of patients conducted separately from treatment.

After a hiatus of some 40 years, clinical research has resumed on the use of classic hallucinogens to treat addiction. Following completion of a small open-label feasibility study, we are currently conducting a double-blind placebo-controlled clinical trial of psilocybin-assisted treatment of alcohol use disorder. Although treatment effects cannot be analyzed until the study is complete, descriptive case studies provide a useful window into the therapeutic process of psychedelic-assisted treatment of addiction. Here we describe treatment trajectories of three participants in the ongoing trial to illustrate the range of experiences and persisting effects of psilocybin treatment. Although it is difficult to generalize from a few cases, several qualitative conclusions can be drawn from the data presented here. Although participants often find it difficult to describe much of their psilocybin experience, pivotal moments tend to be individualized, extremely vivid, and memorable. Often, the qualitative content extends beyond the clinical problem that is being addressed. The participants discussed in this paper experienced acute and lasting alterations in their perceptions of self, in the quality of their baseline consciousness, and in their relationship with alcohol and drinking. In these cases, experiences of catharsis, forgiveness, self-compassion, and love were at least as salient as classic mystical content. Finally, feelings of increased "spaciousness" or mindfulness, and increased control over choices and behavior were reported following the drug administration sessions. Ultimately, psilocybin-assisted treatment appears to elicit experiences that are extremely variable, yet seem to meet the particular needs of the individual.

BACKGROUND: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. METHODS: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. FINDINGS: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0.0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1.36, 95% CI 1.10-1.68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0.44). Opioid-negative urine samples (p<0.0001) and opioid-abstinent days (p<0.0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0.0012), then converged by week 24 (p=0.20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). INTERPRETATION: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications. FUNDING: NIDA Clinical Trials Network.

This chapter reviews what is known about the therapeutic uses of the serotonergic or classic hallucinogens, i.e., psychoactive drugs such as LSD and psilocybin that exert their effects primarily through agonist activity at serotonin 2A (5HT2A) receptors. Following a review of the history of human use and scientific study of these drugs, the data from clinical research are summarized, including extensive work on the use of classic hallucinogens in the treatment of alcoholism and other addictions, studies of the use of LSD and psilocybin to relieve distress concerning death, particularly in patients with advanced or terminal cancer, and more limited data concerning the use of classic hallucinogens to treat mood and anxiety disorders. A survey of possible mechanisms of clinically relevant effects is provided. The well-established safety of classic hallucinogens is reviewed. To provide a clinical perspective, case summaries are provided of two individuals who received treatment in recent controlled trials of psilocybin: one being treated for alcoholism, the other suffering from anxiety and depression related to fear of death due to a cancer diagnosis. Although promising early phase research conducted from the 1950s through the early 1970s was discontinued before firm conclusions could be reached concerning the efficacy of any of the classic hallucinogens for any clinical condition, the research that was conducted in that era strongly suggests that classic hallucinogens have clinically relevant effects, particularly in the case of LSD treatment of alcoholism. In the past decade, clinical trials have resumed investigating the effects of classic hallucinogens in the treatment of existential distress in the face of cancer, and in the treatment of addictions including alcoholism and nicotine addiction. The studies that have been completed to date are not sufficient to establish efficacy, but the outcomes have been very encouraging, and larger trials, up to and including phase 3, are now underway or being planned. Although research has elucidated many of the acute neurobiological and psychological effects of classic hallucinogens on humans, animals, and in vitro systems, the mechanisms of clinically relevant persisting effects remain poorly understood.

We examined the patterns and variability of recovery post-stroke in multiple behavioral domains. A large cohort of first time stroke patients with heterogeneous lesions was studied prospectively and longitudinally at 1-2 weeks, 3 months and one year post-injury with structural MRI to measure lesion anatomy and in-depth neuropsychological assessment. Impairment was described at all timepoints by a few clusters of correlated deficits. The time course and magnitude of recovery was similar across domains, with change scores largely proportional to the initial deficit and most recovery occurring within the first three months. Damage to specific white matter tracts produced poorer recovery over several domains: attention and superior longitudinal fasciculus II/III, language and posterior arcuate fasciculus, motor and corticospinal tract. Finally, after accounting for the severity of the initial deficit, language and visual memory recovery/outcome was worse with lower education, while the occurrence of multiple deficits negatively impacted attention recovery.

A growing field of research explores links between behavioral measures and functional connectivity (FC) assessed using resting-state functional magnetic resonance imaging. Recent studies suggest that measurement of these relationships may be corrupted by head motion artifact. Using data from the Human Connectome Project (HCP), we find that a surprising number of behavioral, demographic, and physiological measures (23 of 122), including fluid intelligence, reading ability, weight, and psychiatric diagnostic scales, correlate with head motion. We demonstrate that "trait" (across-subject) and "state" (across-day, within-subject) effects of motion on FC are remarkably similar in HCP data, suggesting that state effects of motion could potentially mimic trait correlates of behavior. Thus, head motion is a likely source of systematic errors (bias) in the measurement of FC:behavior relationships. Next, we show that data cleaning strategies reduce the influence of head motion and substantially alter previously reported FC:behavior relationship. Our results suggest that spurious relationships mediated by head motion may be widespread in studies linking FC to behavior.