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Psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder: an fMRI pilot study

Pagni, B A; Petridis, P D; Podrebarac, S K; Grinband, J; Claus, E D; Bogenschutz, M P
This pilot study investigated psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder (AUD). Participants were recruited from a phase II, randomized, double-blind, placebo-controlled clinical trial investigating psilocybin-assisted therapy (PAT) for the treatment of AUD (NCT02061293). Eleven adult patients completed task-based blood oxygen dependent functional magnetic resonance imaging (fMRI) approximately 3 days before and 2 days after receiving 25 mg of psilocybin (n = 5) or 50 mg of diphenhydramine (n = 6). Visual alcohol and emotionally valanced (positive, negative, or neutral) stimuli were presented in block design. Across both alcohol and emotional cues, psilocybin increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate, and decreased activity in the insular, motor, temporal, parietal, and occipital cortices, and cerebellum. Unique to negative cues, psilocybin increased supramarginal gyrus activity; unique to positive cues, psilocybin increased right hippocampus activity and decreased left hippocampus activity. Greater PFC and caudate engagement and concomitant insula, motor, and cerebellar disengagement suggests enhanced goal-directed action, improved emotional regulation, and diminished craving. The robust changes in brain activity observed in this pilot study warrant larger neuroimaging studies to elucidate neural mechanisms of PAT.Trial registration: NCT02061293.
PMID: 38326432
ISSN: 2045-2322
CID: 5632302

Reports of self-compassion and affect regulation in psilocybin-assisted therapy for alcohol use disorder: An interpretive phenomenological analysis

Agin-Liebes, Gabrielle; Nielson, Elizabeth M; Zingman, Michael; Kim, Katherine; Haas, Alexandra; Owens, Lindsey T; Rogers, Ursula; Bogenschutz, Michael
OBJECTIVE:The primary aim of this qualitative study was to delineate psychological mechanisms of change in the first randomized controlled trial of psilocybin-assisted psychotherapy to treat alcohol use disorder (AUD). Theories regarding psychological processes involved in psychedelic therapy remain underdeveloped. METHOD/METHODS:Participants (N = 13) mostly identified as non-Hispanic and White, with approximately equal proportions of cisgender men and women. Participants engaged in semistructured interviews about their subjective experiences in the study. Questions probed the nature of participants' drinking before and after the study as well as coping patterns in response to strong emotions, stress, and cravings for alcohol. Verbatim transcripts were coded using Dedoose software, and content was analyzed with interpretive phenomenological analysis. RESULTS:Participants reported that the psilocybin treatment helped them process emotions related to painful past events and helped promote states of self-compassion, self-awareness, and feelings of interconnectedness. The acute states during the psilocybin sessions were described as laying the foundation for developing more self-compassionate regulation of negative affect. Participants also described newfound feelings of belonging and an improved quality of relationships following the treatment. CONCLUSION/CONCLUSIONS:Our results support the assertion that psilocybin increases the malleability of self-related processing, and diminishes shame-based and self-critical thought patterns while improving affect regulation and reducing alcohol cravings. These findings suggest that psychosocial treatments that integrate self-compassion training with psychedelic therapy may serve as a useful tool for enhancing psychological outcomes in the treatment of AUD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
PMID: 37276086
ISSN: 1939-1501
CID: 5610962

Misinterpretations and Omissions: A Critical Response to Goodwin and Colleagues' Commentary on Psilocybin-Assisted Therapy [Letter]

O'Donnell, Kelley C; Anderson, Brian T; Barrett, Frederick S; Bogenschutz, Michael P; Grob, Charles S; Hendricks, Peter S; Kelmendi, Benjamin; Nayak, Sandeep M; Nicholas, Christopher R; Paleos, Casey A; Stauffer, Christopher S; Gukasyan, Natalie
PMID: 38161295
ISSN: 1535-7228
CID: 5625852

Pharmacological and Nonpharmacological Components of Psychedelic Treatments: The Whole is Not the Sum of the Parts [Letter]

Bogenschutz, Michael P
PMID: 38161306
ISSN: 1535-7228
CID: 5625862

Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis

Gold, Noah D; Mallard, Austin J; Hermann, Jacob C; Zeifman, Richard J; Pagni, Broc A; Bogenschutz, Michael P; Ross, Stephen
PMID: 37167080
ISSN: 1557-7740
CID: 5509402

MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial

Mitchell, Jennifer M; Ot'alora G, Marcela; van der Kolk, Bessel; Shannon, Scott; Bogenschutz, Michael; Gelfand, Yevgeniy; Paleos, Casey; Nicholas, Christopher R; Quevedo, Sylvestre; Balliett, Brooke; Hamilton, Scott; Mithoefer, Michael; Kleiman, Sarah; Parker-Guilbert, Kelly; Tzarfaty, Keren; Harrison, Charlotte; de Boer, Alberdina; Doblin, Rick; Yazar-Klosinski, Berra; ,
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. identifier: NCT04077437 .
PMID: 37709999
ISSN: 1546-170x
CID: 5593472

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 (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.
PMID: 37404971
ISSN: 1541-4094
CID: 5539192

Examining the Rationale for Studying Psychedelic-Assisted Psychotherapy for the Treatment of Caregiver Distress

Gold, Noah D; Podrebarac, Samantha K; White, Lindsay A; Marini, Christina; Simon, Naomi M; Mittelman, Mary S; Ross, Stephen; Bogenschutz, Michael P; Petridis, Petros D
ISSN: 2831-4425
CID: 5525822

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.
PMID: 36449315
ISSN: 2168-6238
CID: 5374592

A Systematic Approach to Standardizing Drinking Outcomes From Timeline Followback Data

Marini, Christina; Northover, Nicole S; Gold, Noah D; Rogers, Ursula K; O'Donnell, Kelley C; Tofighi, Babak; Ross, Stephen; Bogenschutz, Michael P
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.
PMID: 36923069
ISSN: 1178-2218
CID: 5606312