In a randomized trial involving 59 selected patients with depression, the change in depression scale scores from baseline to week 6 did not differ significantly between patients who received two ...doses of psilocybin and those who received daily escitalopram. Secondary outcomes generally favored psilocybin over escitalopram.
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of ...depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.
Background:
In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome ...measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR16) did not.
Aims:
The present study aims to (1) rationally and psychometrically account for discrepant results between outcome measures and (2) to overcome psychometric problems particular to individual measures by re-examining between-condition differences in depressive response using all outcome measures at item-, facet-, and factor-levels of analysis.
Method:
Four depression measures were compared on the basis of their validity for examining differences in depressive response between PT and ET conditions.
Results/Outcomes:
Possible reasons for discrepant findings on the QIDS-SR16 include its higher variance, imprecision due to compound items and whole-scale and unidimensional sum-scoring, vagueness in the phrasing of scoring options for items, and its lack of focus on a core depression factor. Reanalyzing the trial data at item-, facet-, and factor-levels yielded results suggestive of PT’s superior efficacy in reducing depressed mood, anhedonia, and a core depression factor, along with specific symptoms such as sexual dysfunction.
Conclusion/Interpretation:
Our results raise concerns about the adequacy of the QIDS-SR16 for measuring depression, as well as the practice of relying on individual scales that tend not to capture the multidimensional structure or core of depression. Using an alternative approach that captures depression more granularly and comprehensively yielded specific insight into areas where PT therapy may be particularly useful to patients and clinicians.
Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of ...psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes.
This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (
= 59). This analysis focused on the psilocybin condition (
= 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called "Accept-Connect-Embody" (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path analyses tested the hypothesis that therapeutic alliance (Scale To Assess the Therapeutic Relationship Patient Version, STAR-P) would predict depression outcomes via its influence on the acute psychedelic experience, specifically emotional-breakthrough (EBI) and mystical-type experiences (MEQ). The same analysis was performed on the escitalopram arm to test specificity.
The strength of therapeutic alliance predicted pre-session rapport, greater emotional-breakthrough and mystical-type experience (maximum EBI and MEQ scores across the two psilocybin sessions) and final QIDS scores (
= -0.22,
= 0.42 for EBI
;
= -0.19,
= 0.32 for MEQ
). Exploratory path models revealed that final depression outcomes were more strongly affected by emotional breakthrough during the first, and mystical experience during the second session. Emotional breakthrough, but not mystical experience, during the first session had a positive effect on therapeutic alliance ahead of the second session (
= 0.79,
< 0.0001). Therapeutic alliance ahead of the second session had a direct impact on final depression scores, not mediated by the acute experience, with a weaker alliance ahead of the second psilocybin session predicting higher absolute depression scores at endpoint (
= -0.49,
< 0.001)
Future research could consider therapist training and characteristics; specific participant factors, e.g., attachment style or interpersonal trauma, which may underlie the quality of the therapeutic relationship, the psychedelic experience and clinical outcomes; and consider how therapeutic approaches might adapt in cases of weaker therapeutic alliance.
This trial is registered at http://clinicaltrials.gov, identifier (NCT03429075).
Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are ...generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with one's partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.
Background:
Psilocybin is a serotonin type 2A (5-HT2A) receptor agonist and naturally occurring psychedelic. 5-HT2A receptor density is known to be associated with body mass index (BMI), however, the ...impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes.
Method:
Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis.
Results:
Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater ‘dread of ego dissolution’ in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not.
Conclusions:
These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.
Background
Major depressive disorder is often associated with maladaptive coping strategies, including rumination and thought suppression.
Aims
To assess the comparative effect of the selective ...serotonin reuptake inhibitor escitalopram, and the serotonergic psychedelic psilocybin (COMP360), on rumination and thought suppression in major depressive disorder.
Method
Based on data derived from a randomised clinical trial (
N
= 59), we performed exploratory analyses on the impact of escitalopram versus psilocybin (i.e. condition) on rumination and thought suppression from 1 week before to 6 weeks after treatment inception (i.e. time), using mixed analysis of variance. Condition responder versus non-responder subgroup analyses were also done, using the standard definition of ≥50% symptom reduction.
Results
A time×condition interaction was found for rumination (F(1, 56) = 4.58,
P
= 0.037) and thought suppression (F(1,57) = 5.88,
P
= 0.019), with
post hoc
tests revealing significant decreases exclusively in the psilocybin condition. When analysing via response, a significant time×condition×response interaction for thought suppression (F(1,54) = 8.42,
P
= 0.005) and a significant time×response interaction for rumination (F(1,54) = 23.50,
P
< 0.001) were evident. Follow-up tests revealed that decreased thought suppression was exclusive to psilocybin responders, whereas rumination decreased in both responder groups. In the psilocybin arm, decreases in rumination and thought suppression correlated with ego dissolution and session-linked psychological insight.
Conclusions
These data provide further evidence on the therapeutic mechanisms of psilocybin and escitalopram in the treatment of depression.
Rationale
Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little ...empirical research has been done to examine the magnitude and nature of its therapeutic role.
Objectives
The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy.
Methods
Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed “liking,” “resonance” (the music being experienced as “harmonious” with the emotional state of the listener), and “openness” (acceptance of the music-evoked experience).
Results
Analyses of the interviews revealed that the music had both “welcome” and “unwelcome” influences on patients’ subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients’ experience of the music was associated with the occurrence of “mystical experiences” and “insightfulness.” Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not.
Conclusions
This study indicates that music plays a central therapeutic function in psychedelic therapy.
Psilocybin is a serotonergic psychedelic drug under assessment as a potential therapy for treatment-resistant and major depression. Heterogeneous treatment responses raise interest in predicting the ...outcome from baseline data.
A machine learning pipeline was implemented to investigate baseline resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI) as a predictor of symptom severity in psilocybin monotherapy for treatment-resistant depression (16 patients administered two 5 mg capsules followed by 25 mg, separated by one week). Generalizability was tested in a sample of 22 patients who participated in a psilocybin vs. escitalopram trial for moderate-to-severe major depression (two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo vs. two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram). The analysis was repeated using both samples combined.
Functional connectivity of visual, default mode and executive networks predicted early symptom improvement, while the salience network predicted responders up to 24 weeks after treatment (accuracy≈0.9). Generalization performance was borderline significant. Consistent results were obtained from the combined sample analysis. Fronto-occipital and fronto-temporal coupling predicted early and late symptom reduction, respectively.
The number of participants and differences between the two datasets limit the generalizability of the findings, while the lack of a placebo arm limits their specificity.
Baseline neurophysiological measurements can predict the outcome of psilocybin treatment for depression. Future research based on larger datasets should strive to assess the generalizability of these predictions.
•Baseline connectivity predicted responders up to 24 weeks after psilocybin treatment.•Visual, default mode and executive networks predicted early improvement.•Salience network was relevant for the prediction of late responders to treatment.•Fronto-occipital and fronto-temporal coupling predicted early and late improvement.
Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action.
In a phase 2, ...double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up.
PT was associated with decreases in neuroticism (
= -0.63), introversion (
= -0.38), disagreeableness (
= -0.47), impulsivity (
= -0.40), and increases in absorption (
= 0.32), conscientiousness (
= 0.30), and openness (
= 0.23) at week 6, with neuroticism (
= -0.47) and disagreeableness (
= -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (
= -0.38), disagreeableness (
= -0.26), impulsivity (
= -0.35), and increases in openness (
= 0.28) at week 6, with neuroticism (
= -0.46) remaining decreased at month 6. No significant between-condition differences were observed.
Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (
ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.
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