Psychedelic-assisted psychotherapy: where is the psychotherapy research?

RATIONALE: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered. OBJECTIVES: As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness. RESULTS: The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding "psychotherapy" versus "psychological support" and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored. CONCLUSIONS: PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.

Psilocybin therapy and anorexia nervosa: a narrative review of safety considerations for researchers and clinicians.

BACKGROUND: Clinical trials using psilocybin therapy to treat anorexia nervosa (AN) are currently underway. The safety and tolerability of psilocybin is of utmost importance in individuals with AN who may present unique medical vulnerabilities. The purpose of this review is to describe how the common physiologic adverse effects of psilocybin may impact medical complications experienced by individuals with AN in clinical trials of psilocybin therapy. MAIN BODY: The physiologic underpinnings of common adverse effects following psilocybin administration are described, including tachycardia, hypertension, electrocardiogram changes, nausea, headache, and lightheadedness. These anticipated physiologic changes are described in relation to the common medical correlates seen in individuals with AN. Risk mitigation strategies for each adverse effect are proposed. CONCLUSION: Early evidence suggests that psilocybin therapy is well-tolerated in individuals with AN. Understanding the unique medical complications of AN, and how they may be impacted by common physiologic adverse effects of psilocybin administration, leads to tailored risk mitigation strategies to enhance safety and tolerability of this novel intervention.

Content analysis of Reddit posts about coadministration of selective serotonin reuptake inhibitors and psilocybin mushrooms.

RATIONALE: Treatments with the serotonergic psychedelic psilocybin are being investigated for multiple neuropsychiatric disorders. Because many patients with these disorders use selective serotonin reuptake inhibitors (SSRIs), understanding interactions between psilocybin and SSRIs is critical for evaluating the safety, efficacy, and scalability of psilocybin-based treatments. Current knowledge about these interactions is limited, as most clinical psilocybin research has prohibited concomittant SSRI use. OBJECTIVES: We aimed to explore potential interactions between psilocybin and SSRIs by characterizing peoples' real-world experiences using psilocybin mushrooms and SSRIs together. METHODS: We conducted a systematic search of Reddit for posts describing psilocybin mushroom and SSRI coadministration. We identified 443 eligible posts and applied qualitative content analysis to each. RESULTS: 8% of posts reported negative physical or psychological effects resulting from coadministration. These included 13 reports that may reflect serotonin toxicity, and 1 concerning for a psychotic/manic episode. 54% of posts described reduced intensity of the acute psilocybin experience, but 39% reported unchanged intensity with SSRI coadministration. CONCLUSIONS: Psilocybin's interactions with SSRIs are likely complex and may depend on multiple factors. Prospective studies are needed to evaluate whether psilocybin treatments are reliably safe and effective in the setting of SSRI use.

"But the reality is it's happening": A qualitative study of eating disorder providers about psilocybin-assisted psychotherapy.

OBJECTIVE: This study invited providers who care for patients with eating disorders to inform engagement, communication, and collaboration with psilocybin-assisted psychotherapy interventions. METHOD: Medical and mental health providers who treat patients with eating disorders were recruited via professional referral networks and participant driven sampling from across California to participate in one of five focus groups. Discussion topics included prior knowledge of psychedelic therapy, interest/concerns related to psilocybin therapy, and opportunities for collaboration. Study team members completed iterative rounds of coding with a grounded theory approach. RESULTS: A total of 32 participants reported a range of familiarity with psychedelics. Some raised concerns about the risks of administering psilocybin to malnourished patients and to those with psychological comorbidities. Despite these concerns, participants were hopeful to see psilocybin therapy as a treatment for patients with eating disorders. In anticipating challenges, providers had concerns about equity in access to care among publicly insured and non-English speaking patients. They requested opportunities for continuing education about psilocybin therapy. DISCUSSION: Our findings demonstrate provider interest in psilocybin therapy for the treatment of patients with eating disorders. As psilocybin therapy interventions are developed, providers caring for patients with eating disorders value collaboration to improve longitudinal patient outcomes. PUBLIC SIGNIFICANCE: This study invited healthcare providers of patients with eating disorders to discuss their thoughts around the use of psilocybin-assisted psychotherapy in this population. Findings will help inform emerging psilocybin therapy clinical trials with the goal of successful translation and adoption in real world clinical settings.

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

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 Registration: ClinicalTrials.gov Identifier: NCT03866174.

MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

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.

Emerging Challenges for Psychedelic Therapy.

This Viewpoint examines the benefits and challenges of psychedelic therapy using 4 fundamental questions.

The effects of intranasal oxytocin on black participants' responses to outgroup acceptance and rejection.

Social acceptance (vs. rejection) is assumed to have widespread positive effects on the recipient; however, ethnic/racial minorities often react negatively to social acceptance by White individuals. One possibility for such reactions might be their lack of trust in the genuineness of White individuals' positive evaluations. Here, we examined the role that oxytocin-a neuropeptide putatively linked to social processes-plays in modulating reactions to acceptance or rejection during interracial interactions. Black participants (N = 103) received intranasal oxytocin or placebo and interacted with a White, same-sex stranger who provided positive or negative social feedback. After positive feedback, participants given oxytocin (vs. placebo) tended to display approach-oriented cardiovascular responses of challenge (vs. threat), exhibited more cooperative behavior, and perceived the partner to have more favorable attitudes toward them after the interaction. Following negative feedback, oxytocin reduced anger suppression. Oxytocin did not modulate testosterone reactivity directly, but our exploratory analysis showed that the less participants suppressed anger during the interaction with their partner, the greater testosterone reactivity they displayed after the interaction. These results survived the correction for multiple testing with a false discovery rate (FDR) of 20%, but not with a rate of 10 or 5%. Discussion centers on the interplay between oxytocin and social context in shaping interracial interactions.

Psilocybin for Trauma-Related Disorders.

Posttraumatic stress disorder (PTSD) is a debilitating, chronic disorder and efficacy rates of current PTSD treatments are underwhelming. There is a critical need for innovative approaches. We provide an overview of trauma and PTSD and cite literature providing converging evidence of the therapeutic potential of psilocybin for PTSD. No study to date has investigated psilocybin or psilocybin-assisted psychotherapy (PAP) as treatments for PTSD. An open-label study in traumatized AIDS survivors found that PAP reduced PTSD symptoms, attachment anxiety, and demoralization. Several PAP trials show preliminary efficacy in facilitating confronting traumatic memories, decreasing emotional avoidance, depression, anxiety, pessimism, and disconnection from others, and increasing acceptance, self-compassion, and forgiveness of abusers, all of which are relevant to PTSD recovery. There is also early evidence that other classic psychedelics may produce large reductions in PTSD symptoms in combat veterans. However, this body of literature is small, mechanisms are not yet well understood, and the risks of using psychedelic compounds for trauma-related disorders need further study. In sum, evidence supports further investigation of PAP as a radically new approach for treating PTSD.

Prior trauma exposure, posttraumatic stress symptoms, and COVID-19 vaccine hesitancy.

Understanding correlates of COVID-19 vaccine intentions is critical for increasing vaccine uptake. Given associations of trauma exposure and posttraumatic stress disorder (PTSD) with alterations in threat sensitivity and health behaviors, we hypothesized they could influence COVID-19 vaccine acceptance and hesitancy and be important variables to consider in the design of vaccination campaigns. Data came from a longitudinal online study of 544 US adults with high levels of pre-pandemic trauma and PTSD, assessed in August/September 2020 and March/April 2021. Individuals reported socio-demographic factors, pandemic factors, lifetime trauma history and PTSD symptoms, and COVID-19 vaccinations or intentions. We estimated bivariate associations between socio-demographics, pandemic factors, and trauma and PTSD symptoms at baseline and follow-up with COVID-19 vaccine acceptance versus hesitancy (i.e., vaccinated against COVID-19 or willing to get vaccinated versus unsure or unwilling to get vaccinated) six months later. Multiple socio-demographics (e.g., race/ethnicity, income, education, political preference) and pandemic factors (e.g., perceived likelihood of infection, household COVID-19 infection) were associated with COVID-19 vaccine hesitancy (27.2% were hesitant). However, trauma history, PTSD symptoms, and other mental health factors were not associated with COVID-19 vaccine acceptance versus hesitancy. Socio-demographic and pandemic-related factors appear more important than trauma or mental health for understanding COVID-19 vaccine intentions.

Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials.

RATIONALE: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research. OBJECTIVE: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research. RESULTS: Although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants' expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy. CONCLUSION: Incorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

Posttraumatic stress disorder symptoms associated with protective and risky behaviors for coronavirus disease 2019.

OBJECTIVE: Psychiatric disorders increase risk for contracting coronavirus disease 2019 (COVID-19), but we know little about relationships between psychiatric symptoms and COVID-19 risky and protective behaviors. Posttraumatic stress disorder (PTSD) has been associated with increased propensity to engage in risky behaviors, but may also be associated with increased COVID-19 protective behaviors due to increased threat sensitivity and social isolation. METHOD: We examined associations of PTSD symptoms with COVID-19-related protective and risky behaviors using data from a cross-sectional online United States study among 845 US adults in August through September 2020. PTSD symptoms (PTSD Checklist-5), sociodemographics, COVID-19-related experiences and vulnerabilities, and past 30-day engagement in 10 protective and eight risky behaviors for COVID-19 were assessed via self-report. We examined associations between PTSD symptoms and COVID-19 protective and risky behaviors with linear regressions, adjusting for covariates. RESULTS: Probable PTSD and higher PTSD symptom severity were associated with greater engagement in protective behaviors, but also greater engagement in risky behaviors. Associations were only slightly attenuated by adjustment for COVID-19 exposures and perceived likelihood and severity of COVID-19. Associations varied by PTSD clusters: intrusions and arousal were associated with both more protective and more risky behaviors, whereas negative cognitions or mood was associated only with more risky, and avoidance only with more protective, behaviors. CONCLUSION: Higher PTSD symptoms were associated with engagement in more protective but also more risky behaviors for COVID-19. Mental health should be considered in the design of public health campaigns dedicated to limiting infectious disease spread. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effects of oxytocin administration on fear-potentiated acoustic startle in co-occurring PTSD and alcohol use disorder: A randomized clinical trial.

Co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and particularly associated with elevation of hyperarousal compared to PTSD alone. Treatment options are limited. Oxytocin regulates physiological stress response. Intranasal oxytocin administration has demonstrated potential in reducing symptoms of both PTSD and AUD. This study addresses a gap in the literature by investigating effects of intranasal oxytocin on startle reactivity, an important potential marker of both PTSD and AUD symptomatology. This is a randomized, double-blind, placebo-controlled, within- and between-participant, crossover, dose-ranging study examining the effects of a single administration of oxytocin 20 IU versus 40 IU versus placebo on psychophysiological responses to a common laboratory fear-potentiated acoustic startle paradigm in participants with PTSD-AUD (n = 47) and controls (n = 37) under three different levels of threat. Contrary to our hypothesis, for the PTSD-AUD group, oxytocin 20 IU had no effect on startle reactivity, while oxytocin 40 IU increased measures of startle reactivity. Additionally, for PTSD-AUD only, ambiguous versus low threat was associated with an elevated skin conductance response. For controls only, oxytocin 20 IU versus placebo was associated with reduced startle reactivity.

Clusters of COVID-19 protective and risky behaviors and their associations with pandemic, socio-demographic, and mental health factors in the United States.

Individual behaviors are critical for preventing the spread of coronavirus disease 2019 (COVID-19) infection. Given that both protective and risky behaviors influence risk of infection, it is critical that we understand how such behaviors cluster together and in whom. Using a data-driven approach, we identified clusters of COVID-19-related protective and risky behaviors and examined associations with socio-demographic, pandemic, and mental health factors. Data came from a cross-sectional online U.S. nationwide study of 832 adults with high levels of pre-pandemic trauma. Latent class analysis was performed with ten protective (e.g., washing hands, wearing masks) and eight risky (e.g., attending indoor restaurants, taking a flight) behaviors for COVID-19. Then, we examined distributions of socio-demographic and pandemic factors across behavior classes using ANOVA or Chi-square tests, and associations between mental health factors (depressive, anxiety, posttraumatic stress symptoms) and behavior classes using multinomial logistic regression. We identified four classes, including three classes with relatively low risky but high (28.8%), moderate (33.5%) and minimal (25.5%) protective behaviors and one high risky behaviors class with associated moderate protective behaviors (12.1%). Age, sexual orientation, political preference, and most pandemic factors differed significantly across behavior classes. Anxiety and posttraumatic stress symptoms, but not depression, were higher in the High Risk, but also Highly and Moderately Protective classes, relative to Minimally Protective. Prevention and intervention efforts should examine constellations of protective and risky behaviors to comprehensively understand risk, and consider current anxiety and posttraumatic stress symptoms as potential risk indicators.

Oxytocin increases physiological linkage during group therapy for methamphetamine use disorder: a randomized clinical trial.

Patients and psychotherapists often exhibit behavioral, psychological, and physiological similarity. Here, we test whether oxytocin-a neuropeptide that can enhance expressivity and social perception-influences time-lagged "linkage" of autonomic nervous system responses among participants and facilitators during group therapy. Physiological linkage estimates (n = 949) were created from ten cohorts, each with two facilitators (n = 5) and four to six participants (n = 48), over six weekly sessions of group therapy for methamphetamine use disorder. All participants of a cohort received oxytocin or placebo intranasally in a randomized double-blind procedure before each session. Cardiac interbeat intervals (IBI) were measured continuously during sessions to estimate physiological linkage, operationalized as one cohort-mate's IBI reactivity during one minute predicting another cohort-mate's IBI reactivity during the following minute. In oxytocin cohorts, participants and facilitators experienced significant physiological linkage to their cohort-mates (i.e., their physiological responses were predicted by the prior responses of their cohort-mates) and significantly more linkage than people in placebo cohorts. Both effects occurred during the first and second sessions but not later sessions. Results suggest that oxytocin may enhance psychosocial processes often associated with linkage-such as social engagement-in groups and highlight oxytocin's potential to improve group cohesion during group therapy.Clinical Trials Registration: NCT02881177, First published on 26/08/2016.

Analysis of Behavior Classification in Motivational Interviewing.

Analysis of client and therapist behavior in counseling sessions can provide helpful insights for assessing the quality of the session and consequently, the client's behavioral outcome. In this paper, we study the automatic classification of standardized behavior codes (i.e. annotations) used for assessment of psychotherapy sessions in Motivational Interviewing (MI). We develop models and examine the classification of client behaviors throughout MI sessions, comparing the performance by models trained on large pretrained embeddings (RoBERTa) versus interpretable and expert-selected features (LIWC). Our best performing model using the pretrained RoBERTa embeddings beats the baseline model, achieving an F1 score of 0.66 in the subject-independent 3-class classification. Through statistical analysis on the classification results, we identify prominent LIWC features that may not have been captured by the model using pretrained embeddings. Although classification using LIWC features underperforms RoBERTa, our findings motivate the future direction of incorporating auxiliary tasks in the classification of MI codes.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

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.

Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience.

Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. Therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. Psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. We hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. We also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. Participants were male long-term AIDS survivors with moderate-severe demoralization (n = 18). Using the Experiences in Close Relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. Clinically important aspects of the psilocybin session were assessed using the revised Mystical Experience Questionnaire and the Challenging Experience Questionnaire the day following psilocybin administration. Self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; d rm = 0.45; 95% CI 0.01, 0.87. Attachment avoidance did not change significantly. Baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. These findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.

Preliminary evidence that oxytocin does not improve mentalizing in women with schizophrenia.

INTRODUCTION: Mentalizing, the ability to infer other people's intentions and emotions, is commonly impaired in schizophrenia and may represent an endophenotype. The hypothalamic neuropeptide oxytocin has been shown to improve mentalizing in men with schizophrenia, but its effects in women remain unclear. Given sex differences in the clinical manifestations of schizophrenia and oxytocin system function, this is an important gap to address. METHODS: We tested the effects of a single-dose oxytocin challenge (40 IU) on mentalizing task performance among 26 women with schizophrenia and 38 healthy control women using a randomized, placebo-controlled, double-blind, crossover design. We aimed to replicate our prior study of oxytocin effects on mentalizing in men with schizophrenia, using the same oxytocin administration procedures and performance-based assessments. We used mixed-effects models and equivalence testing as well as Bayesian hierarchical models to examine oxytocin effects. RESULTS: In contrast to our previous finding in a male sample, oxytocin did not improve mentalizing in this sample of women with schizophrenia. Exploratory analyses showed that higher anti-dopaminergic medication dosage was associated with a decreased response to oxytocin, consistent with previous findings in men. CONCLUSION: These findings provide preliminary evidence that exogenous oxytocin administration may have sex-specific effects on mentalizing in schizophrenia. Inclusion of women in future clinical studies with larger samples is critical, as oxytocin effects observed in men may not extend to women with the disorder.

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study.

BACKGROUND: Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss. METHODS: Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8-10 group therapy visits and one psilocybin administration visit (0·3-0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467). FINDINGS: From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp 2 = 0·47, 90% CI 0·21-0·60). INTERPRETATION: We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs. FUNDING: Carey Turnbull, Heffter Research Institute, NIMH R25 MH060482, NIH UL1 TR001872, River Styx Foundation, Saisei Foundation, Sarlo Foundation, Stupski Foundation, Usona Institute, US Department of Veterans Affairs (Advanced Neurosciences Fellowship and IK2CX001495).