Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review
Kiluk, Brian D; Kleykamp, Bethea A; Comer, Sandra D; Griffiths, Roland R; Huhn, Andrew S; Johnson, Matthew W; Kampman, Kyle M; Pravetoni, Marco; Preston, Kenzie L; Vandrey, Ryan; Bergeria, Cecilia L; Bogenschutz, Michael P; Brown, Randall T; Dunn, Kelly E; Dworkin, Robert H; Finan, Patrick H; Hendricks, Peter S; Houtsmuller, Elisabeth J; Kosten, Thomas R; Lee, Dustin C; Levin, Frances R; McRae-Clark, Aimee; Raison, Charles L; Rasmussen, Kurt; Turk, Dennis C; Weiss, Roger D; Strain, Eric C
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.
Psilocybin for alcohol use disorder: Rationale and design considerations for a randomized controlled trial
O'Donnell, Kelley C; Mennenga, Sarah E; Owens, Lindsey; Podrebarac, Samantha K; Baron, Tara; Rotrosen, John; Ross, Stephen; Forcehimes, Alyssa A; Bogenschutz, Michael P
Several lines of evidence suggest that classic psychedelics (5-HT2A 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 (nâ€¯=â€¯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 25â€¯mg/70â€¯kg psilocybin or 50â€¯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 32â€¯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.
Comparison of self-reported alcohol consumption and ethyl glucuronide in hair in a sample of 60+ year -olds treated for DSM-5 alcohol use disorder
Nielsen, Dorthe GrÃ¼ner; Andersen, Kjeld; Nielsen, Anette SÃ¸gaard; Nielsen, Flemming; Behrendt, Silke; Bilberg, Randi; Bogenschutz, Michael; BÃ¼hringer, Gerhard; Mellentin, Angelina Isabella
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 22â€‰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 â‰¥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 â‰¤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 (ORâ€‰=â€‰1.9, pâ€‰=â€‰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.
Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial
Bogenschutz, Michael P; Ross, Stephen; Bhatt, Snehal; Baron, Tara; Forcehimes, Alyssa A; Laska, Eugene; Mennenga, Sarah E; O'Donnell, Kelley; Owens, Lindsey T; Podrebarac, Samantha; Rotrosen, John; Tonigan, J Scott; Worth, Lindsay
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  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; F1,86â€‰=â€‰6.43; Pâ€‰=â€‰.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.
The Prognostic Role of DSM-5 Alcohol Use Disorder Severity and Age of Onset in Treatment Outcome Among Adults Aged 60
Behrendt, Silke; Kuerbis, Alexis; Mejldal, Anna; Braun-Michl, Barbara; Bilberg, Randi; BÃ¼hringer, Gerhard; Bogenschutz, Michael; Nielsen, Anette SÃ¸gaard; Andersen, Kjeld
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 (nâ€Š=â€Š544) 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: 50â€Šyears; 12-78â€Šyears). 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 (Pâ€Šâ‰¥â€Š0.05). CONCLUSIONS:No indication was found for the need to tailor treatment content according to DSM-5 AUD severity and earlier onset in older adults.
A randomized clinical trial of strengths-based case management to link emergency department patients to opioid use disorder treatment
Bogenschutz, Michael P; McCormack, Ryan; Rapp, Richard; Meyers-Ohki, Sarah; Mennenga, Sarah E; Regis, Amber; Kolaric, Rhonda; Glisker, Richard; Greco, Peter P
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 2Â days of self-reported opioid misuse in the 4Â 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, pÂ >Â 0.05), nor did engagement in pharmacotherapy differ significantly between groups (pÂ >Â 0.05). During the 90Â days following the index ED visit, SBCM and SAR participants engaged in pharmacotherapy for a mean of 21.8% (SDÂ =Â 35.1%) versus 17.7% (SDÂ =Â 31.0%) of days, respectively. Likewise, no significant difference occurred between groups in rates of "successful opioid use outcome" as defined a priori (pÂ >Â 0.05), although self-reported opioid use over the entire 6-month follow-up period was lower in the SBCM group (10.8 vs. 13.4Â days/month, pÂ =Â 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.
Residual alcohol use disorder symptoms after treatment predict long-term drinking outcomes in seniors with DSM-5 alcohol use disorder
Behrendt, Silke; Kuerbis, Alexis; Braun-Michl, Barbara; Bilberg, Randi; BÃ¼hringer, Gerhard; Bogenschutz, Michael; Mejldal, Anna; Andersen, Kjeld; SÃ¸gaard Nielsen, Anette
BACKGROUND:Risk of relapse within the first months after alcohol use disorder (AUD) interventions is substantial among older adults. For this vulnerable group, little information exists on how this risk is associated with residual DSM-5 AUD symptoms after treatment. AIMS/OBJECTIVE:To investigate among older adults who received short-term treatment for DSM-5 AUD (1) the prediction of drinking behaviors and quality of life 12Â months after treatment initiation by 6-month DSM-5 AUD symptoms, AUD severity, and AUD remission, and (2) whether these DSM-5 AUD indicators provide prognostic information beyond that gained from 6-month alcohol use (AU) status. METHODS:The international multicenter RCT "ELDERLY-Study" enrolled adults aged 60+ with DSM-5 AUD. We used data from the subsample of 323 German and Danish participants with complete DSM-5 AUD criterion information 6 months after treatment initiation (61% male; mean age = 65.5Â years). AU was assessed with Form 90, DSM-5 AUD with the M.I.N.I., and quality of life with the WHOQOL-BREF. Generalized linear models were applied to investigate the associations between 6-month AUD indicators and 12-month AU and quality of life. RESULTS:Independent of AU at 6 months, having 1 (vs. no) residual AUD symptom at 6 months predicted a 12-month "slip," defined as exceeding a blood alcohol concentration of 0.05% at least once during that time (OR: 3.7, 95% CI: 1.5 to 9.0), heavy episodic drinking, and hazardous use (pÂ <Â 0.05). AUD remission was associated with a lower risk of a "slip" at 12 months (pÂ <Â 0.05). Failed reduction/cessation was associated with poorer physical health (Coef.: -0.4, 95% CI -0.7 to -0.1). CONCLUSION/CONCLUSIONS:For older adults, residual AUD symptoms in the first months after short-term treatment predict problematic AU outcomes during the first 12Â months after treatment entry. Thus, residual symptoms should be addressed in this patient population during posttreatment screenings.
Spiritual experiences in psychedelic-assisted psychotherapy: Case reports of communion with the divine, the departed, and saints in research using psilocybin for the treatment of alcohol dependence.
Podrebarac, Samantha K.; O'Donnell, Kelley C.; Mennenga, Sarah E.; Owens, Lindsey T.; Malone, Tara C.; Duane, Jessie H.; Bogenschutz, Michael P.
Psychedelic substances have been central to religious and shamanic healing practices of various cultures for generations. More recently, in western medicine, psychedelic substances have demonstrated promise in the treatment of various mental health indications. A growing evidence base supports not only the therapeutic potential of psychedelic-assisted psychotherapy, but also the importance of integrating spiritual aspects of psychedelic experiences into the traditional therapeutic process. Psilocybin, a classic psychedelic, is a serotonergic hallucinogen that can elicit profound spiritual experiences even in the research setting. Our group is currently conducting a randomized controlled trial exploring the therapeutic potential of psilocybin-assisted psychotherapy for alcohol dependence. Over the course of the trial, many individuals have reported experiences that take a variety of forms, including spiritual insights, beatific visions, and communion with the Divine. Here we present three case studies of experiences involving communion with a deceased loved one, with a holy figure, and with the Divine from our clinical trial. These cases have been selected to illustrate the diverse nature of the spiritual experiences observed in this clinical trial, and to also explore elements of spiritual care that may be supportive in the psychotherapeutic process during and after the medication experiences. Should psychedelic medicine continue to show treatment promise in clinical trial stages, there is a strong possibility that these medicines will become an integral part of psychotherapy, which will require integration of direct spiritual experiences and spiritual care into the healing process. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study
Mitchell, Jennifer M; Bogenschutz, Michael; Lilienstein, Alia; Harrison, Charlotte; Kleiman, Sarah; Parker-Guilbert, Kelly; Ot'alora G, Marcela; Garas, Wael; Paleos, Casey; Gorman, Ingmar; Nicholas, Christopher; Mithoefer, Michael; Carlin, Shannon; Poulter, Bruce; Mithoefer, Ann; Quevedo, Sylvestre; Wells, Gregory; Klaire, Sukhpreet S; van der Kolk, Bessel; Tzarfaty, Keren; Amiaz, Revital; Worthy, Ray; Shannon, Scott; Woolley, Joshua D; Marta, Cole; Gelfand, Yevgeniy; Hapke, Emma; Amar, Simon; Wallach, Yair; Brown, Randall; Hamilton, Scott; Wang, Julie B; Coker, Allison; Matthews, Rebecca; de Boer, Alberdina; Yazar-Klosinski, Berra; Emerson, Amy; Doblin, Rick
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 (nâ€‰=â€‰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 2â€‰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 (Pâ€‰<â€‰0.0001, dâ€‰=â€‰0.91) and to significantly decrease the SDS total score (Pâ€‰=â€‰0.0116, dâ€‰=â€‰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.
Stability of Posttreatment Reductions in World Health Organization (WHO) Drinking Risk Levels and Posttreatment Functioning in Older Adults with DSM-5 Alcohol Use Disorder: Secondary Data Analysis of the Elderly Study
Mejldal, Anna; Andersen, Kjeld; Behrendt, Silke; Bilberg, Randi; Bogenschutz, Michael; Braun-Michl, Barbara; BÃ¼hringer, Gerhard; SÃ¸gaard Nielsen, Anette
BACKGROUND:Studies have found that reductions in World Health Organization (WHO) drinking risk levels may be a stable outcome of treatment for alcohol use disorder (AUD) and associated with functional improvements. The aim of this study was to investigate whether posttreatment reductions in WHO drinking risk levels are stable over time among older adults and associated with a decrease in consequences of drinking and AUD symptoms and improved quality of life. METHODS:Participants. Individuals 60+Â years old, suffering from DSM-5 AUD (nÂ =Â 693), and seeking outpatient treatment. MEASUREMENTS:WHO drinking risk levels, prior to treatment and at all follow-up points up to 1Â year after treatment start, were assessed with Form 90. Outcomes at follow-up included consequences of drinking (Drinker Inventory of Consequences), quality of life (WHOQOL-BREF), and DSM-5 AUD symptoms (Mini International Neuropsychiatric Interview). Logistic regression and linear mixed models were used to examine the probability of maintaining risk-level reductions at follow-up and the association between risk-level reductions and outcomes, respectively. RESULTS:Reductions in risk levels were maintained over time (at least 1 level: OR 5.39, 95% CI 3.43, 8.47; at least 2 levels: OR 9.30, 95% CI 6.14, 14.07). Reductions were associated with reduced consequences of drinking and number of AUD symptoms, and minor, but statistically significant, improvements in quality of life. CONCLUSIONS:Maintaining reductions in WHO risk levels appears achievable for older adults seeking treatment for AUD. The small reduction of AUD symptoms and improvement of quality of life indicates that these reductions may not be adequate as the only treatment goal.