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Older adults in psychedelic-assisted therapy trials: A systematic review

Bouchet, Lisa; Sager, Zachary; Yrondi, Antoine; Nigam, Kabir B; Anderson, Brian T; Ross, Stephen; Petridis, Petros D; Beaussant, Yvan
BACKGROUND/UNASSIGNED:Growing clinical interest in psychedelic-assisted therapies has led to a second wave of research involving psilocybin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA) and other substances. Data suggests that these compounds have the potential to treat mental health conditions that are especially prevalent in older adults such as depression, anxiety, existential distress, and posttraumatic stress disorder. AIMS/UNASSIGNED:The goal of this study was to quantify the prevalence of older adults enrolled in psychedelic clinical trials and explore safety data in this population. METHODS/UNASSIGNED:A systematic review was conducted following the 2020 PRISMA guidelines. Search criteria included all trials published in English using psychedelic substances to treat psychiatric conditions, including addiction as well as existential distress related to serious illness. Articles were identified from literature searches on PubMed, EBSCO, and EMBASE. RESULTS/UNASSIGNED:4376 manuscripts were identified, of which 505 qualified for further review, with 36 eventually meeting eligibility criteria. Of the 1400 patients enrolled in the 36 studies, only 19 were identified as 65 or older, representing less than 1.4% of all trial participants. For 10 of these 19 older adults, detailed safety data was obtained. No serious adverse events (AEs) occurred in any older adults and only transient mild-to-moderate AEs related to anxiety, gastrointestinal upset, and hypertension were reported during the psychedelic dosing sessions. CONCLUSIONS/UNASSIGNED:While existing data in older adults is limited, it suggests that psychedelic-assisted psychotherapy can be safe and well tolerated in older adults. Therefore, psychedelic-assisted psychotherapy should be more rigorously investigated for the treatment of psychiatric conditions in this population.
PMID: 38240068
ISSN: 1461-7285
CID: 5628842

Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder

Zeifman, Richard J; Kettner, Hannes; Ross, Stephen; Weiss, Brandon; Mithoefer, Michael C; Mithoefer, Ann T; Wagner, Anne C
PMID: 38174611
ISSN: 2000-8066
CID: 5626092

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

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial

Raison, Charles L; Sanacora, Gerard; Woolley, Joshua; Heinzerling, Keith; Dunlop, Boadie W; Brown, Randall T; Kakar, Rishi; Hassman, Michael; Trivedi, Rupal P; Robison, Reid; Gukasyan, Natalie; Nayak, Sandeep M; Hu, Xiaojue; O'Donnell, Kelley C; Kelmendi, Benjamin; Sloshower, Jordan; Penn, Andrew D; Bradley, Ellen; Kelly, Daniel F; Mletzko, Tanja; Nicholas, Christopher R; Hutson, Paul R; Tarpley, Gary; Utzinger, Malynn; Lenoch, Kelsey; Warchol, Kasia; Gapasin, Theraysa; Davis, Mike C; Nelson-Douthit, Courtney; Wilson, Steffanie; Brown, Carrie; Linton, William; Ross, Stephen; Griffiths, Roland R
IMPORTANCE:Psilocybin shows promise as a treatment for major depressive disorder (MDD). OBJECTIVE:To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. DESIGN, SETTING, AND PARTICIPANTS:In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. INTERVENTIONS:Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. MAIN OUTCOMES AND MEASURES:The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. RESULTS:A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. CONCLUSIONS AND RELEVANCE:Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. TRIAL Identifier: NCT03866174.
PMID: 37651119
ISSN: 1538-3598
CID: 5606332

Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences

Zeifman, Richard J; Kettner, Hannes; Pagni, Broc A; Mallard, Austin; Roberts, Daniel E; Erritzoe, David; Ross, Stephen; Carhart-Harris, Robin L
Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose-response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.
PMID: 37608057
ISSN: 2045-2322
CID: 5596732

Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs

Zia, Farah Z; Baumann, Michael H; Belouin, Sean J; Dworkin, Robert H; Ghauri, Majid H; Hendricks, Peter S; Henningfield, Jack E; Lanier, Ryan K; Ross, Stephen; Berger, Ann
Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".
PMID: 37015315
ISSN: 1873-7064
CID: 5502672

Letter to the Editor: What Is in a Name? The Many Meanings of Psychedelic

O'Donnell, Kelley C.; Roberts, Daniel E; Ching, Terence H.W.; Glick, Gianni; Goldway, Noam; Gukasyan, Natalie; Hokansen, Jamila; Kelmendi, Benjamin; Ross, Stephen; Yaden, Mary E.; Pittenger,Christopher
ISSN: 2831-4425
CID: 5545112

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

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

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 (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.
PMID: 36332827
ISSN: 1559-2030
CID: 5358872