This randomized clinical trial examines the efficacy of psilocybin as an adjunct to psychotherapy and other treatments for major depressive disorder.

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin. Studies suggest that psilocybin, a classic psychedelic drug (serotonin 2A or 5-HT 2A receptor partial agonist), may have efficacy for the treatment of depression and anxiety 1-3 , tobacco use disorder 4,5 , and alcohol use disorder 6,7. Reduction of clinical symptoms has been shown to last up to 3 3 , 6 1,2 , and 12 8 months after 1 to 3 psilocybin administrations. Despite these promising advances, the neural and psychological mechanisms underlying the enduring therapeutic effects of psychedelic drugs are not well-understood. Two possibly interactive trans-diagnostic targets that may be affected by psilocybin are negative affect and brain network plasticity. Increased negative affect, reduced positive affect, and hypersensitivity to negatively biased information are hallmarks of mood disorders 9-11. Negative affect is also a core component of the cycle of addiction in which craving and withdrawal symptoms experienced after intoxication lead to preoccupation, anticipation, and re-administration of drugs of abuse 12. The amygdala has been shown in clinical and preclinical models to track the salience of stimuli in the environment 13,14 and is highly responsive to negative emotional stimuli 15-17. Abnormally high amygdala reactivity to negative affective stimuli has been implicated in the pathophysiology of depression 18. Areas within the anterior cingulate cortex (ACC) are understood to monitor cognitive conflict 19-22 , are involved in the appraisal and expression of negative emotion 22 , respond to distress levels associated with pain 23 ...

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes. Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin. Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21–75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed through 12 months following their second dose. Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression. Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

This study examined how psychedelics reduced symptoms of racial trauma among black, indigenous, and people of color (BIPOC) subsequent to an experience of racism. A cross-sectional internet-based survey included questions about experiences with racism, mental health symptoms, and acute and enduring psychedelic effects. Changes in mental health were assessed by retrospective report of symptoms in the 30 days before and 30 days after an experience with psilocybin, Lysergic acid diethylamide (LSD), or 3,4-Methylenedioxymethamphetamine (MDMA). We recruited 313 diverse BIPOC in the US and Canada. Results revealed a significant ( p < .001) and moderate (d = −.45) reduction in traumatic stress symptoms from before-to-after the psychedelic experience. Similarly, participants reported decreases in depression ( p < .001; d = −.52), anxiety ( p < .001; d = −.53), and stress ( p < .001; d = −.32). There was also a significant relationship (R c = 0.52, p < .001) between the dimension of acute psychedelic effects (mystical-type, insight, and challenging experiences) and decreases in a cluster of subsequent psychopathology (traumatic stress, depression, anxiety, and stress), while controlling for the frequency of prior discrimination and the time since the psychedelic experience. BIPOC have been underrepresented in psychedelic studies. Psychedelics may decrease the negative impact of racial trauma. Future studies should examine the efficacy of psychedelic-assisted therapy for individuals with a history of race-based trauma.

Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans. Method We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%). Results Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives. Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary. Conclusion U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.

Background Previous research showed acute psychedelic effects were associated with decreases in racial trauma (RT) symptoms among black, indigenous, and people of color (BIPOC). Among samples comprised primarily of white participants, positive outcomes of psychedelic experiences have been mediated by increases in psychological flexibility. Therefore, we examined whether changes in psychological flexibility from before to after a psychedelic experience mediated the relationship between acute psychedelic effects and changes in RT symptoms among BIPOC. Methods This cross-sectional online survey study included 313 BIPOC (mean age = 33.1; SD = 11.2; female = 57%). A multiple linear regression analysis was used to examine the association between acute psychedelic effects and decreases in RT symptoms in a nonclinical setting; a path analysis was used to explore whether changes in psychological flexibility mediated this relationship. Results Acute insight and challenging effects were significantly ( p < .001) associated with decreases in RT symptoms following a psychedelic experience. Increases in psychological flexibility partially mediated relationships between greater intensity of psychological insight and less intensity of challenging experiences and decreases in RT symptoms ( ps<.001). Conclusion This research suggests psychedelics confer potential benefits in decreasing RT symptoms among BIPOC and psychological flexibility may be an important mediator of these effects. Future research should test this hypothesis in a longitudinal clinical trial among BIPOC.

Background and aims 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent, short-acting psychedelic that produces strong hallucinogenic effects. The association between the context (i.e., set and setting) of 5-MeO-DMT use and the acute and enduring effects of the substance is unknown. Therefore, this study examined these associations using secondary data from two cross-sectional survey studies. Methods The acute and enduring effects of inhaled synthetic 5-MeO-DMT were compared between individuals who used 5-MeO-DMT in a non-structured context (NSC; n = 216, female = 10%, Mage = 35.5, SD = 11.8) and those who used in a structured context (SC; n = 362, female = 45%, Mage = 47.7, SD = 13.3). Questionnaires were administered online and responses were anonymized for privacy purposes. Respondents were asked to retrospectively rate their first experience with synthesized 5-MeO-DMT on measures of mystical experience, challenging experience, and enduring effects. Results Both groups endorsed high ratings on the Mystical Experience Questionnaire; however, mean scores were significantly higher in the SC group compared to the NSC group. Similarly, the proportion of respondents who had a complete mystical experience was significantly larger in the SC group (83%) compared to the NSC group (54%). Ratings of enduring effects (i.e., meaningfulness, spirituality, and well-being) were also significantly higher, and the intensity of challenging experiences was significantly lower, in the SC group compared to the NSC group. Conclusions 5-MeO-DMT appears to occasion mystical-type experiences with enduring positive effects, which are more intense when 5-MeO-DMT is administered in a safe and supportive context. Future prospective experimental studies should examine the effects of 5-MeO-DMT and its interactive relationship with supportive contextual factors.