Faculty Bibliography

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

IMPORTANCE/UNASSIGNED:Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. OBSERVATIONS/UNASSIGNED:Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

OBJECTIVE/UNASSIGNED:The timeline followback (TLFB) interview is the gold standard for the quantitative assessment of alcohol use. However, self-reported "drinks" can vary in alcohol content. If this variability is not accounted for, it can compromise the reliability and validity of TLFB data. To improve the precision of the TLFB data, we developed a detailed standard operating procedure (SOP) to calculate standard drinks more accurately from participant reports. METHOD/UNASSIGNED:For the new SOP, the volume and alcohol content by volume (ABV) of distinct types of alcoholic beverages were determined based on product websites and other reliable sources. Recipes for specific cocktails were constructed based on recipes from bartending education websites. One standard drink was defined as 0.6 oz (14 g) of absolute alcohol. Standard drink totals were contrasted for the new SOP approach and the standard procedure, which generally assumed that one self-reported drink was equivalent to one standard drink. RESULTS/UNASSIGNED:Relative to the standard TLFB procedure, higher numbers of standard drinks were reported after implementing the TLFB SOP. CONCLUSIONS/UNASSIGNED:Variability in procedures for conversion of self-reported alcohol consumption to standard drinks can confound the interpretation of TLFB data. The use and reporting of a detailed SOP can significantly reduce the potential for such inconsistencies. Detailed and consistent procedures for calculation of standard drinks can enhance the quality of TLFB drinking data.

Several lines of evidence suggest that classic psychedelics (5-HT_2A receptor agonists or partial agonists) such as psilocybin might facilitate behavior change in individuals with substance use disorders. We conducted a multi-site, double-blind, randomized controlled trial (RCT) to assess the effects of psilocybin-assisted psychotherapy in alcohol-dependent volunteers. In addition to a structured 12-week psychotherapy platform, participants (n = 96) were randomly assigned (1:1) to receive either oral psilocybin or an active placebo (oral diphenhydramine) in each of two dosing sessions (at weeks 4 and 8). Initial doses were 25 mg/70 kg psilocybin or 50 mg diphenhydramine, which could be increased in the second session depending on initial response. The psychotherapy platform combined evidence-based, manualized therapy for alcohol dependence with a supportive context for the dosing sessions. All participants were followed in the RCT through week 36. At the end of the RCT, participants who still met safety criteria were offered an open-label psilocybin session. Data collected at screening, baseline and throughout the study included: demographics, measures of alcohol use, subjective response to psilocybin and diphenhydramine, and safety measures. The primary outcome was the proportion of heavy drinking days during the 32 weeks after the first dosing session (i.e., between week 4 and week 36). Secondary outcomes included safety, additional measures of drinking (e.g., abstinence, drinking days, etc.), craving, self-efficacy, and acute effects. We will also explore moderators and mediators of the primary outcome. The primary outcomes will be published elsewhere. In this paper, we describe the protocol and rationale for our design decisions.

There is a lack of evidence for the consistency between self-reported alcohol consumption (SRAC) and concentrations of ethyl glucuronide in hair (hEtG) among elderly patients treated exclusively for alcohol use disorder (AUD). Hence, this study assessed the consistency between these two measures in these patients. A total of 190 patients with AUD were assessed for SRAC using Form 90 and hEtG, 14 or 22 weeks after treatment conclusion. Patients were grouped according to SRAC (g/day) and corresponding hEtG concentrations (pg/mg): 0 and <5 (abstinence), 0.1-14.3 and 5.0-9.9 (low consumption), 14.4-21.4 and 10.0-15.9 (moderate consumption), 21.5-59.9 and 16.0-30 (high consumption) and ≥60 and >30 (excessive consumption). The extent of underreporting and overreporting was examined by crosstabulations, and inter-rater reliability was reported by kappa correlations. Associations and effect modification were examined by conditional logistic regression. Due to multitesting, p-values ≤0.01 were considered significant. Underreporting was found in 96 patients (50.5%) and overreporting in 41 patients (21.6%). The kappa coefficients varied between 0.19 and 0.34. HEtG was more likely to detect low, moderate and high alcohol consumption compared with SRAC (ORs between 5.1 and 12.6, all p-values <0.01), but SRAC and hEtG did not differ significantly with respect to identification of abstinence (OR = 1.9, p = 0.05). Inconsistency between the outcome measures was found in a considerable number of the patients. More studies examining the consistency between SRAC and specific direct biomarkers of alcohol in this population seem warranted.

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.

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.