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Papers

Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness

Abstract

Background: With support from the Radcliffe Institute for Advanced Study at Harvard University, we convened researchers representing palliative care, psychosocial oncology, spiritual care, oncology, and psychedelic-assisted therapies. We aimed to define priorities and envision an agenda for future research on psychedelic-assisted therapies in patients with serious illness. Over two days in January 2020, participants engaged in an iterative series of reflective exercises that elicited their attitude and perspectives on scientific opportunities for this research. Objectives: The aim of the study is to identify themes that shape priorities and an agenda for research on psychedelic-assisted therapy for those affected by serious illness. Methods: We collected data through preconference interviews, audio recordings, flip charts, and sticky notes. We applied thematic qualitative analysis to elucidate key themes. Results: We identified seven key opportunities to advance the field of psychedelic-assisted therapies in serious illness care. Four opportunities were related to the science and design of psychedelic-assisted therapies: clarifying indications; developing and refining therapeutic protocols; investigating the impact of set and setting on therapeutic outcomes; and understanding the mechanisms of action. The other three pertained to institutional and societal drivers to support optimal and responsible research: education and certification for therapists; regulations and funding; and diversity and inclusion. Additionally, participants suggested epistemological limitations of the medical model to understand the potential value and therapeutic use of psychedelics. Conclusions: Medicine and society are witnessing a resurgence of interest in the effects and applications of psychedelic-assisted therapies in a wide range of settings. This article suggests key opportunities for research in psychedelic-assisted therapies for those affected by serious illness.

Beaussant, Y., Tulsky, J., Guérin, B., Schwarz-Plaschg, C., Sanders, J. J., & Radcliffe Institute for Advanced Study Working Group on Psychedelic Research in Serious Illness (2021). Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness. Journal of palliative medicine, 24(11), 1657–1666. https://doi.org/10.1089/jpm.2020.0764

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Spontaneous and deliberate creative cognition during and after psilocybin exposure

Abstract

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Mason, N. L., Kuypers, K., Reckweg, J. T., Müller, F., Tse, D., Da Rios, B., Toennes, S. W., Stiers, P., Feilding, A., & Ramaekers, J. G. (2021). Spontaneous and deliberate creative cognition during and after psilocybin exposure. Translational psychiatry, 11(1), 209. https://doi.org/10.1038/s41398-021-01335-5

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Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies

Abstract

Background: 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake.

Methods: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA.

Results: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait “openness to experience” predicted more perceived “closeness”, a stronger decrease in “general inactivation”, and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales “oceanic boundlessness” and “visionary restructuralization”, and (c) subjects with high “neuroticism” or trait anxiety were more likely to have unpleasant and/or anxious reactions.

Conclusions: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.

Studerus, E., Vizeli, P., Harder, S., Ley, L., & Liechti, M. E. (2021). Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies. Journal of psychopharmacology (Oxford, England), 35(5), 556–565. https://doi.org/10.1177/0269881121998322

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Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression

Abstract

Objectives: Accumulating evidence has implicated that brain derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of depression, but its correlation with ketamine’s antidepressant efficacy focusing on Chinese individuals with depression is not known. This study was aim to determine the correlation of plasma BDNF (pBDNF) concentrations and ketamine’s antidepressant efficacy.

Methods: Ninety-four individuals with depression received six intravenous infusions ketamine (0.5 mg/kg). Remission and response were defined as Montgomery-Asberg Depression Rating Scale (MADRS) scores less than 10 and a reduction of 50% or more in MADRS scores, respectively. Plasma was collected at baseline and at 24 h and 2 weeks after completing six ketamine infusions (baseline, 13 d and 26 d).

Results: A significant improvement in MADRS scores and pBDNF concentrations was found after completing six ketamine infusions compared to baseline (all ps < 0.05). Higher baseline pBDNF concentrations were found in ketamine responders/remitters (11.0 ± 6.2/10.1 ± 5.8 ng/ml) than nonresponders/nonremitters (8.0 ± 5.5/9.2 ± 6.4 ng/ml) (all ps < 0.05). Baseline pBDNF concentrations were correlated with MADRS scores at 13 d (t = – 2.011, p = 0.047) or 26 d (t = – 2.398, p = 0.019) in depressed patients (all ps < 0.05). Subgroup analyses found similar results in individuals suffering from treatment refractory depression.

Conclusion: This preliminary study suggests that baseline pBDNF concentrations appeared to be correlated with ketamine’s antidepressant efficacy in Chinese patients with depression.

Zheng, W., Zhou, Y. L., Wang, C. Y., Lan, X. F., Zhang, B., Zhou, S. M., Yan, S., & Ning, Y. P. (2021). Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression. PeerJ, 9, e10989. https://doi.org/10.7717/peerj.10989

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LSD and ketanserin and their impact on the human autonomic nervous system

Abstract

The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug-induced effects in a randomized, placebo-controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R-peak-based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD-induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.

Olbrich, S., Preller, K. H., & Vollenweider, F. X. (2021). LSD and ketanserin and their impact on the human autonomic nervous system. Psychophysiology, 58(6), e13822. https://doi.org/10.1111/psyp.13822

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Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Abstract

Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.

Agin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS pharmacology & translational science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018

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Examining changes in personality following shamanic ceremonial use of ayahuasca

Abstract

The present study examines the association between the ceremonial use of ayahuasca-a decoction combining the Banistereopsis caapi vine and N,N-Dimethyltryptamine-containing plants-and changes in personality traits as conceived by the Five-Factor model (FFM). We also examine the degree to which demographic characteristics, baseline personality, and acute post-ayahuasca experiences affect personality change. Participants recruited from three ayahuasca healing and spiritual centers in South and Central America (N = 256) completed self-report measures of personality at three timepoints (Baseline, Post, 3-month Follow-up). Informant-report measures of the FFM were also obtained (N = 110). Linear mixed models were used to examine changes in personality and the moderation of those changes by covariates. The most pronounced change was a reduction in Neuroticism dzself-reportT1-T2 = – 1.00; dzself-reportT1-T3 = – .85; dzinformant-reportT1-T3 = – .62), reflected in self- and informant-report data. Moderation of personality change by baseline personality, acute experiences, and purgative experiences was also observed.

Weiss, B., Miller, J. D., Carter, N. T., & Keith Campbell, W. (2021). Examining changes in personality following shamanic ceremonial use of ayahuasca. Scientific reports, 11(1), 6653. https://doi.org/10.1038/s41598-021-84746-0

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Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Dos Santos, R. G., Hallak, J. E., Baker, G., & Dursun, S. (2021). Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action. Journal of psychopharmacology (Oxford, England), 35(4), 453–458. https://doi.org/10.1177/0269881120986422

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Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer

Abstract

People with advanced cancer are at heightened risk of desire for hastened death (DHD), suicidal ideation (SI), and completed suicide. Loss of Meaning (LoM), a component of demoralization, can be elevated by a cancer diagnosis and predicts DHD and SI in this population. We completed a randomized controlled trial in which psilocybin-assisted psychotherapy (PAP) produced rapid and sustained improvements in depression, demoralization, and hopelessness in people with cancer. Converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment. To probe our hypothesis that PAP relieves SI through its beneficial impacts on depression and demoralization (LoM in particular), we performed secondary analyses assessing within- and between-group differences with regard to LoM and an SI composite score. Among participants with elevated SI at baseline, PAP was associated with within-group reductions in SI that were apparent as early as 8 h and persisted for 6.5 months postdosing. PAP also produced large reductions in LoM from baseline that were apparent 2 weeks after treatment and remained significant and robust at the 6.5 month and 3.2 and 4.5 year follow-ups. Exploratory analyses support our hypothesis and suggest that PAP may be an effective antisuicidal intervention following a cancer diagnosis due to its positive impact on hopelessness and demoralization and its effects on meaning-making in particular. These preliminary results implicate psilocybin treatment as a potentially effective alternative to existing antidepressant medications in patients with cancer that are also suicidal, and warrant further investigation in participants with elevated levels of depression and suicidality.

Ross, S., Agin-Liebes, G., Lo, S., Zeifman, R. J., Ghazal, L., Benville, J., Franco Corso, S., Bjerre Real, C., Guss, J., Bossis, A., & Mennenga, S. E. (2021). Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer. ACS pharmacology & translational science, 4(2), 553–562. https://doi.org/10.1021/acsptsci.1c00020

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Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice

Abstract

Psychedelic and mindfulness interventions have been shown to improve mental ill-health and wellbeing, with a range of clinical processes and effects in common. However, each appear to contain specific challenges in the context of mental health treatment. In this Perspective, we focus on a set of distinct affordances, “useful differences”, within psychedelic and mindfulness interventions that might address common challenges within the other intervention. Accordingly, we propose a set of applied synergies, indicating specific ways in which these two promising interventions might be combined for greater benefit. Metaphorically, on the journey toward mental health and wellbeing, we propose that psychedelic treatments may serve the role of Compass (initiating, motivating, and steering the course of mindfulness practice), with mindfulness interventions serving the role of Vehicle (integrating, deepening, generalizing, and maintaining the novel perspectives and motivation instigated by psychedelic experience). We outline a set of testable hypotheses and future research associated with the synergistic action of psychedelic and mindfulness interventions toward improved clinical outcomes.

Payne, J. E., Chambers, R., & Liknaitzky, P. (2021). Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice. ACS pharmacology & translational science, 4(2), 416–423. https://doi.org/10.1021/acsptsci.1c00034

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