Epistemic Risk Reduction in Psychedelic-Assisted Therapy.

Belief change is crucial to therapeutic benefit in psychedelic-assisted therapy as well as in more traditional forms of therapy. However, the use of psychedelics comes with a few unique challenges that require extra caution. First, drastic belief changes may occur faster than in regular therapy. Facing radical and transformative insights all at once rather than through a gradual process of discovery and integration can lead patients to a volatile, confusing or disorienting epistemic state. Additionally, we know psychedelic substances generate hallucinatory experiences that come with a high degree of confidence and noetic certainty despite not necessarily being connected with reality. On the other hand, telling a patient which ones of her beliefs are true and which ones are not seems beyond the competence of a psychotherapist, if not an abuse of their authority and power. This is even more dangerous when psychedelics are involved, because power imbalance between patient and therapist is exacerbated by the therapist's role as a guiding figure throughout an intense altered state of consciousness. Because of this suggestible state, the therapist's beliefs might have a disproportionate influence, and even well-intentioned nudging might significantly stray the patient's beliefs.How can a therapist help a patient navigate their epistemic uncertainty around psychedelic insights while preserving the patient's autonomy? This chapter will attempt to answer this question through a philosophical and epistemological lens. We will review different strategies to mitigate epistemic risks in psychedelic-assisted therapy and argue that such risks can be significantly reduced by adapting these strategies dynamically to the individual patient's needs.

Does the Perception of Risk Associated with Psychedelics Use Differ in Physicians According to Their Belief of Effectiveness?

The aim of this study was to explore the perception of psychedelics within the medical population. Participants were asked by questionnaire about the potential of abuse, the somatic and psychiatric complications, and the risks of self-harm and aggression associated with the use of psychedelics using Likert Scales. A total of 407 participants were included. In our sample, the following means were found: 3.05 for general risk (<.001), 2.68 for self-harm risk (<.001), 2.47 for aggression (<.001), 2.71 for addictive risk (< .001), 2.76 for psychiatric disorder risk (<.001), and 2.11 for somatic disorder(< .001). Physicians from the lower mean of age were significantly more supportive of therapeutic potential, while general practitioners were significantly less likely to consider psychedelics as a treatment than specialists (<.001). By the term therapeutic potential, we meant the therapeutic value attributable to psychedelics and the risks expressed the possibility of damage caused by the use of the drug. Clinicians who considered psychedelics as a potential treatment were less likely to associate these with risks than their counterparts (<.001). The results of this study show that the perception of the danger of psychedelic use was important in the medical community in France.

Impact of psilocybin on cognitive function: A systematic review.

Psilocybin is a classic psychedelic with demonstrated preliminary clinical efficacy in a range of psychiatric disorders. Evaluating the impact of psilocybin on cognitive function is essential to unravel its potential benefits and risks. In this systematic review, we assessed psilocybin's effect on cognitive function through a comprehensive search of electronic databases from inception to January 2024, identifying 20 articles involving 2,959 participants. While 85% of studies were conducted in healthy volunteers, most of these studies (85%) used macrodoses, ranging from 45 µg/kg to 30 mg/70 kg. Various cognitive aspects were evaluated and yielded mixed results. Global cognitive function, and processing speed remained mostly unchanged in healthy individuals; However, a limited number of studies reported improvements in certain areas such as sustained attention, working memory, and executive function especially in patients with treatment-resistant depression (TRD). Emotional processing was positively modified, particularly in TRD patients. Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive flexibility and creative cognition were noted to initially decline but could potentially improve over time. Additionally, with respect to learning and memory skills, psilocybin showed promise in improving specific memory types such as semantic associations and associative learning, while its effects on episodic and verbal memory have been less pronounced compared to other cognitive enhancers. The observed mixed findings underscore the complexity of psilocybin's cognitive influence. Further research is essential to provide a clearer understanding of psilocybin's impact on cognitive domains and to guide the development of safe and effective interventions.

Psilocybin reduces functional correlation and the encoding of spatial information by neurons in mouse retrosplenial cortex.

Psychedelic drugs have profound effects on perception, cognition and mood. How psychedelics affect neural signaling to produce these effects remains poorly understood. We investigated the effect of the classic psychedelic psilocybin on neural activity patterns and spatial encoding in the retrosplenial cortex of head-fixed mice navigating on a treadmill. The place specificity of neurons to distinct locations along the belt was reduced by psilocybin. Moreover, the stability of place-related activity across trials decreased. Psilocybin also reduced the functional correlation among simultaneously recorded neurons. The 5-HT2AR (serotonin 2A receptor) antagonist ketanserin blocked these effects. These data are consistent with proposals that psychedelics increase the entropy of neural signaling and provide a potential neural mechanism contributing to disorientation frequently reported by humans after taking psychedelics.

History, Hype, and Responsible Psychedelic Medicine: A Qualitative Study of Psychedelic Researchers.

Background Psychedelic medicine is a rapidly growing area of research and policy change. Australia recently became the first country to legalize the prescription of psychedelics and serves as a case study of issues that may emerge in other jurisdictions. Despite their influence as a stakeholder group, there has been little empirical exploration of psychedelic researchers' views on the development of psychedelic research and the ethical concerns. Methods We thematically analysed fourteen interviews with Australian psychedelic researchers. Results Three themes were constructed from the data: 1) coming out of the shadow of the 1960s, 2) challenges and affordances in engaging stakeholders, and 3) growing pains in innovation and translation. Conclusion The results illustrated tensions arising from the rapid growth of psychedelic research from a small group of dedicated individuals with a similar worldview, to a multi-interest, regulated industry. Participants' experiences and viewpoints were influenced by the history of psychedelic research, and this was met with an overarching concern for protecting the field from premature discontinuation, as well as maximizing potential positive impacts. Targets for stakeholder collaboration and initiatives to support responsible innovation in psychedelics include equitable access, sustainable industry involvement, productive research agendas, responsible reporting of evidence, and risk-taking within the relative safety of clinical trials.

Latin American adults who regularly use macrodoses of psychedelics: a cross-sectional study.

Psychedelics have a complex history marked by traditional use among indigenous cultures, early scientific interest, and subsequent prohibition. Despite their classification as controlled substances, recent decades have witnessed a resurgence of research into their therapeutic potential for various mental health conditions. However, most studies have focused on controlled clinical settings, leaving a significant gap in understanding how these substances are used in naturalistic contexts, particularly in Latin America. This study investigates the regular use of macrodoses of psychedelics among Latin American adults. We aimed to characterize the sociodemographic profiles, consumption practices, and subjective effects experienced by individuals who use psychedelics regularly. Data were collected via an online survey from 4,270 participants across several Latin American countries. Results indicated a diverse user base with varied motivations, predominantly psychological and spiritual well-being. The most frequently used substance was psilocybin mushrooms, with significant associations found between demographic variables and specific psychedelics used. The study provides new insights into the naturalistic use of psychedelics in Latin America, highlighting the need for informed, safe, and legal use frameworks.

The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression.

It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study's primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.

Beyond the numbers: reimagining healing with psychedelics for eating disorders.

Psychedelic medicine is currently being evaluated for numerous mental health indications, and there is significant interest in applying these models of care to eating disorders (EDs) given the limited efficacy of available treatment models, especially for those living with anorexia nervosa. Preliminary findings across a number of studies suggest promise. In this commentary, researchers with experience in psychedelics and EDs present a rationale and considerations for the application of psychedelic medicine, including psychedelic-assisted therapy (PAT) for EDs. These contributions are informed by those with lived experience as well as the authors' experiences in the field. By addressing underlying psychological and transpersonal factors and improving treatment engagement, psychedelic medicine, though not without risks, may offer a valuable adjunct to existing treatments, enhancing overall outcomes for some living with an ED. This commentary also aims to provide a multi-dimensional perspective to inform the field, including with respect to the etiology of these illnesses, as psychedelic medicine becomes more accessible in naturalistic, research and clinical settings.

Co-use of psychedelics with other substances: Findings from the global psychedelic survey.

BACKGROUND/AIMS: While most psychedelic substances are considered to carry a relatively low risk of acute or long-term harm, co-use with other psychoactive substances may increase health and social harm. Using a large international survey of adults who use psychedelics, we sought to comprehensively characterize psychedelic co-use. METHODS: We used data from the 2023 Global Psychedelic Survey, a web-based survey of adults ⩾21 with lifetime use of psychedelics. We explored patterns of co-use (prevalence, secondary substances used, timing, and motives of co-use) and examined sociodemographic and psychedelic use-related characteristics associated with co-use overall and by specific psychedelics. RESULTS: In total, 5370 respondents were included in this analysis, of whom 3228 (56.3%) reported typically co-using at least one of the 11 psychedelic substances of interest, with co-use lowest for ayahuasca (14.8%) and highest for nitrous oxide (54.5%). Cannabis and alcohol were the most common secondary substances. Depressants were the only secondary substance class that increased in use following psychedelic experiences. Greater experience with psychedelics was significantly associated with co-use, as was using for recreational purposes or to reduce/substitute the use of other substances. Personal exploration and therapeutic purposes for psychedelic use were negatively associated with co-use. CONCLUSIONS: In this detailed analysis of psychedelic co-use, we observed high rates of co-use with certain psychedelics, specifically when used recreationally. Our findings highlight psychedelic-specific consumers for whom harm reduction messaging around co-use practices may be best tailored. Further research is justified to assess whether specific patterns of co-use might reduce or increase potential harms.

From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression.

Social cognitive deficits and social behavior impairments are common in major depressive disorder (MDD) and affect the quality of life and recovery of patients. This review summarizes the impact of standard and novel treatments on social functioning in MDD and highlights the potential of combining different approaches to enhance their effectiveness. Standard treatments, such as antidepressants, psychotherapies, and brain stimulation, have shown mixed results in improving social functioning, with some limitations and side effects. Newer treatments, such as intranasal oxytocin, mindfulness-based cognitive therapy, and psychedelic-assisted psychotherapy, have demonstrated positive effects on social cognition and behavior by modulating self-referential processing, empathy, and emotion regulation and through enhancement of neuroplasticity. Animal models have provided insights into the neurobiological mechanisms underlying these treatments, such as the role of neuroplasticity. Future research should explore the synergistic effects of combining different treatments and investigate the long-term outcomes and individual differences in response to these promising interventions.

Expert recommendations for Germany's integration of psychedelic-assisted therapy.

As clinical trials for psychedelics move into phase III in the USA, Europe must address its lag in integrating professional education around psychedelic-assisted therapy (PAT) and supporting psychedelic drug research. This paper evaluates the necessary frameworks for implementing PAT in Germany, emphasizing the nation's potential leadership role within the European Union. With Australia having already approved MDMA and psilocybin for mental health indications, the Ukrainian government exploring MDMA treatment for war-related PTSD, and initial clinical trials involving MDMA and LSD with patients in Switzerland which restarted the restricted medical use of these substances around 2014, the medical authorization of psychedelics in these countries establishes precedent showcasing both the promise and challenges of researching and implementing PAT in nations where the substances were formally scheduled as illicit substances. Key challenges include establishing rigorous standards for practitioner training, accessibility, and defining regulatory oversight. This paper focuses on the development of robust infrastructure in Germany, which will support the roll out of PAT, and details ethical considerations, training protocols, and governmental roles in the formulation of treatment frameworks. This approach aims not only to guide Germany in adopting PAT but also to influence broader European policy, ensuring that patients receive ethically sound and proficient care. The findings suggest pathways for Europe to reclaim its historical lead in psychiatric and therapeutic innovation.

Psilocybin for major depressive disorder: An updated systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Due to the unsatisfactory therapeutic effects of current antidepressants, research has been launched into alternative treatment approaches, such as the administration of psychedelics. Psilocybin, a classic hallucinogen, has been shown to exert considerable positive influence on depression symptoms through its serotonergic and glutamatergic effects. This systematic review and meta-analysis aimed to evaluate the effectiveness of psilocybin in treating depression. METHODS: A comprehensive search of Medline (via PubMed) and the Cochrane Library databases was conducted to identify relevant studies. Inclusion criteria were applied to select studies that investigated the therapeutic impact of psilocybin on depression. A mixed-effects multi-level model was used to estimate the overall effect size. Effectiveness over time was also investigated as a secondary analysis. RESULTS: The results of the primary analysis revealed a large and clinically observable reduction (SMC: -1.24, 95%CI: -1.83 to -0.65, I2level2 = 11.39%, I2level3 = 77.67%) of depressive symptomatology in patients receiving psilocybin in addition to supportive therapy compared to baseline measurements. The decrease was also marked when compared to placebo (p-value = 0.032). The results remained significant even when a secondary analysis assessed the effect in various time intervals since the administration of psilocybin. CONCLUSION: This systematic review and meta-analysis substantiate the claim that psilocybin is superior in treating depression compared to established psychotherapy alone used for treating depression. This finding warrants further studies with larger sample sizes and across a longer timeframe.

Anxiety and Affective Symptoms Related to the Use of Classic Psychedelics: A Systematic Review.

There is a large and rapidly growing body of literature investigating the therapeutic effects of classic psychedelics in affective and anxiety disorders, but very few studies have examined the inverse of this, that is, the potential for psychedelics to inflict anxiety and affective symptoms. A systematic literature search was performed and 39 papers were included in the final review to qualitatively synthesize the current literature on anxiety and affective disorders related to the use of classic psychedelics. Persisting disorders were less frequent but generally occurred in individuals who presented with several risk factors (overdose, polydrug use, unstructured recreational setting, psychosocial stress, personal/familial psychiatric histories). When psychedelics were administered in clinical studies under the framework of psychedelic-assisted therapy, the incidence of enduring anxiety and affective symptoms was low. In most cases, acute transient anxiety emerged and resolved during the dosing session without the need for additional treatment interventions. The nuance of such cases is discussed, shedding light on the role of emotional catharsis in the therapeutic process. Several suggestions are proposed to enhance patient safety including strengthening the therapeutic alliance, ensuring adequate mental preparation, acclimating to high doses and providing on-going therapeutic support.

Acceptance as a possible link between past psychedelic experiences and psychological flexibility.

Increased psychological flexibility (PF) may underlie the lasting positive effects of psychedelic experiences on mental well-being. The associations between different components of PF, psychological inflexibility (PI), and well-being with psychedelic use are not well understood. We conducted a cross-sectional internet survey of participants (N = 629) with experience of classical psychedelics. Using network analysis, we examined how aspects of a single psychedelic experience (mystical-type features and psychological insights) and the frequency of past psychedelic use, were associated with current PF and PI components, as well as with mental well-being and ill-being. Mediation analyses explored whether PF mediated the relationship between past psychedelic use and well-being or ill-being. The network analysis linked psychological insight to the PF component Acceptance, with no association found between the frequency of past use and PF. Mediation analyses showed PF mediates the association between past psychedelic use and well-being and ill-being. These results suggest that the quality and depth of the psychedelic experience, rather than the frequency of use, are primarily linked to psychological flexibility, particularly Acceptance, and overall well-being. This underscores the importance of treating PF as a multidimensional construct to better understand the long-term mental health benefits of psychedelics.

Psychedelics and the treatment of eating disorders: considerations for future research and practice.

Recent trials have shown promising results for the use of psychedelic-assisted therapies in treating severe refractory psychiatric illnesses, and there has been growing interest in examining the effectiveness of these therapies in treating eating disorders. To move forward in a safe, ethically sound, and scientifically rigorous manner, the field must address critical considerations. In this Comment article, we outline important risks and ethical considerations, along with methodological aspects that require careful consideration in the design of psychedelic-assisted therapy trials. We conclude by providing provisional guidelines for clinical research trials to help shape the future of this work, with the aim of investigating and employing the use of psychedelics for treating eating disorders in a manner that protects clients and research participants while maximizing methodological rigour.

Psychedelic-related deaths in England, Wales and Northern Ireland (1997-2022).

BACKGROUND: Psychedelic drugs are increasingly visible in society once more, but their risks and adverse effects have received less attention than perhaps they should. While fatalities associated with psychedelics appear rare, a systematic approach to characterising their aetiology is required to inform harm minimisation efforts. AIMS: This study aimed to analyse prevalence and characteristics of psychedelic-related deaths in England, Wales, and Northern Ireland, between 1997 and 2022. METHODS: We analysed coroner reports submitted to the National Programme on Substance Use Mortality where psychedelic serotonergic agonist drugs were involved in the death, and conducted a thematic framework analysis to explore potential factors associated with their occurrence. RESULTS: We identified 28 cases where psychedelics were implicated (75 %, N = 21) or potentially implicated (25 %, N = 7) in the death; 19 of these involving psychedelic tryptamines (LSD 39 %, N = 11; Psilocybin 21 %, N = 6; DMT 7 %, N = 2), and 9 psychedelic phenethylamines (incl. NBOMes 18 %, N = 5). Most deaths were deemed accidental by the coroner (86 %, N = 24), including both traumatic injuries and drug toxicities; most cases involved multiple implicated drugs (68 %, N = 19); and most of the deceased were under 30 years of age (82 %, N = 23). Thematic framework analysis identified nine themes in the deaths across three categories. 'Polysubstance use' was the most common theme (82 % of cases, N = 23/28), followed by a suboptimal 'physical environment' (70 % of cases where this information was available, N = 14/20). CONCLUSIONS: The profound and often unpredictable effects of psychedelics pose a unique profile of risks and adverse reactions. Nevertheless, psychedelic-related deaths remain very rare in comparison to other recreational drugs, and frequently involve polydrug use. Implications for harm reduction and policy are discussed.

Psilocybin-assisted neurofeedback for the improvement of executive functions: a randomized semi-naturalistic-lab feasibility study.

Executive function deficits, common in psychiatric disorders, hinder daily activities and may be linked to diminished neural plasticity, affecting treatment and training responsiveness. In this pioneering study, we evaluated the feasibility and preliminary efficacy of psilocybin-assisted frontal-midline theta neurofeedback (NF), a neuromodulation technique leveraging neuroplasticity, to improve executive functions (EFs). Thirty-seven eligible participants were randomized into an experimental group (n = 18) and a passive control group (n = 19). The experimental group underwent three microdose sessions and then three psilocybin-assisted NF sessions, without requiring psychological support, demonstrating the approach's feasibility. NF learning showed a statistical trend for increases in frontal-midline theta from session to session with a large effect size and non-significant but medium effect size dynamical changes within sessions. Placebo effects were consistent across groups, with no tasks-based EF improvements, but significant self-reported gains in daily EFs-working memory, shifting, monitoring and inhibition-showing medium and high effect sizes. The experimental group's significant gains in their key training goals underscored the approach's external relevance. A thorough study with regular sessions and an active control group is crucial to evaluate EFs improvement and their specificity in future. Psilocybin-enhanced NF could offer significant, lasting benefits across diagnoses, improving daily functioning. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.