[Are psychedelics fast acting antidepressant agents?] / Sind Psychedelika schnell wirksame Antidepressiva?

BACKGROUND: Psychedelics, such as psilocybin represent one of the most promising current therapeutic approaches in psychiatry. OBJECTIVE: Psychedelics seem to have not only potent antidepressant effects. Do they also work particularly quickly, i.e. within one day? MATERIAL AND METHODS: The available literature on clinical studies of psychedelics in depressive syndromes is presented both from the period up to the prohibition of these substances in the late 1960s as well as after the resumption of research in the 2000s. One focus is the speed of onset of antidepressant action. RESULTS: Only the clinical studies published since 2016 that meet modern methodological standards have also systematically examined the speed of the antidepressant onset of action. The published studies, which were almost exclusively carried out with psilocybin, so far show small sample sizes (the total number of patients with depression treated in published clinical studies is < 200) and some of them have methodological weaknesses; however, they suggest a pronounced and very rapid onset of action within one day for depression, treatment-resistant depression and depression in the context of life-threatening cancer. CONCLUSION: The available studies indicate a potent, rapid onset and in many cases long-lasting antidepressant effect over several months. The currently conducted studies with three-digit patient numbers will provide final information about the potential of psilocybin for depression.

Classical Psychedelics as Therapeutics in Psychiatry - Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders.

Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.

Treatment with psychedelics is psychotherapy: beyond reductionism.

Treatment of psychiatric disorders with psychedelic substances represents one of the most promising current treatment approaches in psychiatry. Since its inception in the 1950s, therapy with psychedelics has been conceptualised as psychedelic-assisted psychotherapy-ie, a form of psychotherapy that uses the profound biological effects of this class of substances as a catalyst for changing thinking, emotions, and behaviour. In this view, the psychotherapy component of the treatment is considered as being of the utmost importance for both the safety and efficacy of the therapy. This conceptualisation has been challenged by the idea that the latest clinical studies suggest that the potential therapeutic effects of psychedelics must be attributed solely to the substance itself, with no role for psychotherapy. Here, accompaniment by therapists is understood as mere psychological support, to maintain the safety of the substance administration. In this Personal View, we contrast these two views and argue that the characterisation of treatment with psychedelics as a biological intervention (with psychological support as a purely safety-related component) represents an outdated and reductionistic dualism that has dominated psychiatric treatment and research for far too long. This discussion has important implications for the study and the regulation of these compounds.

Measuring psychotherapeutic processes in the context of psychedelic experiences: Validation of the General Change Mechanisms Questionnaire (GCMQ).

BACKGROUND: Therapeutic and salutogenic effects of psychedelic drugs have been attributed to psychotherapeutic or psychotherapy-like processes that can unfold during the acute psychedelic experience and beyond. Currently, there are no psychometric instruments available to comprehensively assess psychotherapeutic processes (as conceptualized by empirical psychotherapy research) in the context of psychedelic experiences. AIMS: We report the initial validation of the General Change Mechanisms Questionnaire (GCMQ), a self-report instrument designed to measure five empirically established general change mechanisms (GCMs) of psychotherapy-(1) resource activation, (2) therapeutic relationship, (3) problem actuation, (4) clarification, and (5) mastery-in the context of psychedelic experiences. METHODS: An online survey in a sample of 1153 English-speaking and 714 German-speaking psychedelic users was conducted to evaluate simultaneously developed English- and German-language versions of the GCMQ. RESULTS: The theory-based factor structure was confirmed. The five GCMQ scales showed good internal consistency. Evidence for convergent validity with external measures was obtained. Significant associations with different settings and with therapeutic, hedonic, and escapist use motives confirmed the hypothesized context dependence of GCM-related psychedelic experiences. Indicating potential therapeutic effects, the association between cumulative stressful life events and well-being was significantly moderated by resource activation, clarification, and mastery. Factor mixture modeling revealed five distinct profiles of GCM-related psychedelic experiences. CONCLUSION: Initial testing indicates that the GCMQ is a valid and reliable instrument that can be used in future clinical and nonclinical psychedelic research. The five identified profiles of GCM-related experiences may be relevant to clinical uses of psychedelics and psychedelic harm reduction.

The Acceptance/Avoidance-Promoting Experiences Questionnaire (APEQ): A theory-based approach to psychedelic drugs' effects on psychological flexibility.

BACKGROUND: Many benefits and some harms associated with psychedelic use could be attributable to these drugs' acceptance/avoidance-promoting effects and corresponding changes in psychological flexibility. Underlying psychological mechanisms are insufficiently understood. AIM: The purpose of this study was the validation of a psychological model of acceptance/avoidance-promoting psychedelic experiences, which included the development of a theory-based self-report instrument: the Acceptance/Avoidance-Promoting Experiences Questionnaire (APEQ). Its two main scales, acceptance-related experience (ACE) and avoidance-related experience (AVE), represent the theorized model's core constructs. We aimed to test the model's central assumptions of complementarity (ACE and AVE may occur alternatingly but not simultaneously, and are therefore empirically independent), intertwinedness (subaspects within ACE and AVE are mutually contingent and therefore highly inter-correlated), context-dependence (ACE and AVE depend on context factors) and interaction (longer-term outcomes depend on the interplay between ACE and AVE). METHOD: A bilingual retrospective online survey including 997 English- and 836 German-speaking participants. Each participant reported on one psychedelic experience occasioned by lysergic acid diethylamide (LSD), psilocybin, mescaline, or ayahuasca. RESULTS: Whereas ACE and AVE were found to be relatively independent aspects of participants' reported psychedelic experiences (complementarity), their subaspects were mostly distinguishable but strongly correlated among each other (intertwinedness). Therapeutic, escapist, and hedonic use motives were differentially associated with ACE and AVE (context-dependence), which were in turn associated with retrospective changes in psychological flexibility following participants' reported experiences. The positive association between ACE and increased psychological flexibility was significantly moderated by AVE (interaction). CONCLUSION: These results provide an initial validation of the APEQ and its underlying theoretical model, suggesting the two can help clarify the psychological mechanisms of psychedelic-induced benefits and harms. Both should be further investigated in prospective-longitudinal and clinical studies.

Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience.

INTRODUCTION: As their name suggests, 'psychedelic' (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). METHODS: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific 'global psychedelic survey' study. RESULTS: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach's α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. CONCLUSION: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight - as measured by the PIS - was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Childhood Maltreatment, Borderline Personality Features, and Coping as Predictors of Intimate Partner Violence.

Intimate partner violence (IPV) is a serious mental and physical health concern worldwide. Although previous research suggests that childhood maltreatment increases the risk for IPV, the underlying psychological mechanisms of this relationship are not yet entirely understood. Borderline personality (BP) features may play an important role in the cycle of violence, being associated with interpersonal violence in both childhood and adult relationships. The present study investigated whether BP features mediate the relationship between childhood maltreatment and IPV, differentiating between perpetration and victimization, and taking maladaptive stress coping and gender into account. Self-reports on IPV, childhood trauma, BP features, and maladaptive stress coping were collected in a mixed (nonclinical and clinical) sample of 703 adults (n = 537 female, n = 166 male), using an online survey. A serial mediation analysis (PROCESS) was performed to quantify the direct effect of childhood maltreatment on IPV and its indirect effects through BP features and maladaptive coping. Childhood maltreatment severity significantly positively predicted IPV perpetration as well as victimization. BP features, but not coping, partially mediated this relationship. Follow-up analyses suggest that affective instability and interpersonal disturbances (e.g., separation concerns) play an important role in IPV perpetration, while interpersonal and identity disturbances may mediate the effect of childhood maltreatment on IPV victimization. In clinical practice, attention should be paid not only to histories of childhood abuse and neglect but also to BP features, which may be possible risk factors for IPV.

Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse.

For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run. Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model. In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention. In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.

Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance.

The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.

Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation.

Psychedelic therapy shows promise as a novel intervention for a wide range of mental health concerns but its therapeutic action is incompletely understood. In line with acceptance and commitment therapy's (ACT's) transdiagnostic model, qualitative research has suggested that reductions in experiential avoidance are an important component of therapeutic outcomes associated with psychedelics. However, limited research has quantitatively explored the association between decreases in experiential avoidance and therapeutic outcomes associated with psychedelics. Therefore, in two prospective studies, using convenience samples of individuals with plans to use a psychedelic, we explored the impact of psychedelic use on experiential avoidance, depression severity, and suicidal ideation, as well as relationships between changes in these outcomes. Participants (Study 1, N=104; Study 2, N=254) completed self-report questionnaires of depression severity, suicidal ideation, and experiential avoidance: 1) before using a psychedelic (in ceremonial and non-ceremonial contexts), as well as 2) 2-weeks and 3) 4-weeks after psychedelic use. Across both studies, repeated measures ANOVAs indicated significant decreases in experiential avoidance, depression severity, and suicidal ideation after psychedelic use. Furthermore, decreases in experiential avoidance were significantly associated with decreases in depression severity and suicidal ideation. These results suggest that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation. Additionally, these findings imply that reduced experiential avoidance may be a transdiagnostic mechanism mediating treatment success within psychedelic therapy. We conclude that integrating psychedelics with psychotherapeutic interventions that target experiential avoidance (e.g. ACT) may enhance therapeutic outcomes.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression.

BACKGROUND: Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy. AIMS: Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin. METHODS: Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week. RESULTS: Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing. CONCLUSION: These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.