Cortical high-frequency oscillations (≈ 110 Hz) in cats are state-dependent and enhanced by a subanesthetic dose of ketamine.

Ketamine is an NMDA receptor antagonist that has antidepressant and anesthetic properties. At subanesthetic doses, ketamine induces transient psychosis in humans, and is used to model psychosis in experimental animals. In rodents, subanesthetic doses of ketamine increase the power of high-frequency oscillations (HFO, > 100 Hz) in the electroencephalogram (EEG), a frequency band linked to cognitive functions. However, to date, the effects of ketamine in carnivores and primates have been poorly investigated. Here, we examined in the cat, cortical HFO during wakefulness, sleep, and after administering a sub-anesthetic dose of ketamine. Four cats were prepared with cortical electrodes for chronic polysomnographic recordings in head-restrained conditions. The cortical HFO power, connectivity, direction of the information flow using Granger Causality (GC) analysis, their relationships with respiratory activity, and the effect of auditory stimulation were analyzed. During wakefulness, but not during sleep, we found that HFO were coupled with the inspiratory phase of the respiration. After ketamine administration, HFO power was enhanced and remained associated with the inspiratory phase. GC analysis suggests that ketamine-enhanced HFO originate from the olfactory bulb (OB) and stream towards the prefrontal cortex (Pf). Accordingly, occluding the nostrils significantly reduced the power of the ketamine-enhanced HFO in both the OB and Pf. Finally, auditory stimulation did not affect HFO. In conclusion, the HFO are associated with respiration during wakefulness, but not during sleep. The enhancement of this rhythm by ketamine may disrupt cortical information processing, which could contribute to some of the neuropsychiatric effects associated with ketamine.

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.

Australian psychologists' attitudes towards psychedelic-assisted therapy and training following a world-first drug down-scheduling.

INTRODUCTION: This study explores the attitudes of psychologists towards psychedelics and psychedelic-assisted therapy (PAT) following the world-first regulatory changes in 2023 in Australia which permitted psilocybin and 3,4-methylenedioxy-methamphetamine (MDMA) to be used in clinical services. METHODS: A purposive sample of 20 Australian psychologists was recruited using snowball sampling. Semi-structured interviews were conducted which explored participants' attitudes, knowledge and concerns about PAT. Data were coded and analysed to identify and develop theme categories. RESULTS: Most psychologists exhibited positive attitudes towards psychedelics and their therapeutic potential, viewing them as promising for addressing chronic mental health conditions like depression. However, there was a notable concern regarding the limited evidence on efficacy and potential adverse experiences, as well as the complexity of the individualised treatment protocol. Despite enthusiasm, many psychologists had limited detailed knowledge about the interventions themselves. The need for comprehensive education and training programs, including exposure to psychedelic experiences and credible higher education institutions, was emphasised to ensure competence in administering PAT. DISCUSSION AND CONCLUSIONS: Psychologists displayed notably positive attitudes towards PAT, likely reflecting both shifting perceptions of psychedelics and self-selection bias within the sample. Despite this optimism, concerns were raised about psychiatric risks and the necessity for comprehensive and reputable training and supervision. The cohort showed openness to both novel treatments and innovative training methods, underscoring the importance of enhancing educational frameworks to ensure effective implementation of PAT.

Defined radio wave frequencies attenuate the head-twitch response in mice elicited by (±)-2,5-dimethoxy-4-iodoamphetamine.

Results from clinical trials show that serotonergic psychedelics have efficacy in treating psychiatric disorders, where currently approved pharmacotherapies are inadequate. Developing psychedelic medicines, however, comes with unique challenges, such as tempering heightened anxiety associated with the psychedelic experience. We conceived a new strategy to potentially mitigate psychedelic effects with defined electromagnetic signals (ES). We recorded the electromagnetic fields emitted by the serotonin 2 receptor (5-HT2R) agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and converted them to a playable WAV file. We then exposed the DOI WAV ES to mice to assess its effects on the DOI-elicited, 5-HT2AR dependent head-twitch response (HTR). The DOI WAV signal significantly attenuated the HTR in mice elicited by 0.1 and 0.3 mg/kg subcutaneous DOI (p < 0.05 and p < 0.01, respectively). A scrambled WAV signal did not affect the DOI-elicited HTR, suggesting specificity of the DOI WAV signal. These results provide evidence that defined ES could modulate the psychoactive effects of serotonergic psychedelics. We discuss putative explanations for the distinct effects of the DOI WAV signal in the context of previous studies that demonstrate ES's efficacy for treating other conditions, including pain and cancer.

Numerous clinical studies demonstrate that psychedelic drugs can treat psychiatric disorders. A challenge with psychedelic drugs is that they can elicit distressing experiences, which require psychological support in some patients. Recent developments have allowed for the recording of the electromagnetic shell or field of molecules in solution. These electromagnetic signals (ES) can be emitted (as a magnetic field) to emulate the effects of the recorded drug. By using ES, we have the potential to manage or mitigate the negative effects of a drug, simply by turning off the magnetic field. The main target of serotonergic psychedelic drugs is the serotonin receptor, 5-HT_2A. A reliable and well-studied drug used in psychedelic research is (±)-2,5-dimethoxy-4-iodoamphetamine (DOI). DOI binds and activates the 5-HT_2A receptor. DOI is known to elicit head twitching in mice (called the head-twitch response or HTR) that is indicative of 5-HT_2A receptor activation. A recording of DOI was played to evaluate its effect on the head-twitch response in mice. Here we report that the DOI WAV signal decreased the head-twitch response observed after treating mice with the DOI drug. The effects were measurable, reproducible and demonstrated the ability of the DOI recording to dampen the head-twitch response. This WAV recording has the potential to interfere with the unwanted effects of psychedelics, making their use safer.

Ketamine-induced altered states of consciousness: a systematic review of implications for therapeutic outcomes in psychiatric practices.

This systematic review aims to elucidate the nexus between ketamine's psychoactive properties and its efficacy in treating a broad spectrum of psychiatric disorders. We searched three databases and used citation tracking to include 29 studies. Predominantly, mood disorders, including bipolar disorder (BD) and major depressive disorder (MDD) (MDD + BD: + n = 25 studies), a large part of them involve treatment-resistant patients (n = 14 studies), substance use disorder (SUD, n = 3 studies), and social anxiety disorder (SAD, n = 1 study). From all included studies (n = 29), 15 (51.72%) of them identified a positive relation between ketamine-induced altered states of consciousness and clinical outcomes, while 13 studies (44.83%) showed no linkage between them, and one study (3.45%) delineated a negative association. Focusing solely on intravenous (IV) ketamine infusions (n = 25), 14 studies (56%) reported a positive modulation of ketamine's psychoactive effects and therapeutic benefits, whereas 10 studies (40%) confirmed no relationship, and one study (4%) showed a negative association. The single study (33.34%) involving subcutaneous ketamine and all three studies (66.6%) intranasal administration did not demonstrate a significant interaction between ketamine's psychoactive effects and therapeutic response. All three SUD studies reported a positive correlation between ketamine's psychoactive effects and therapeutic response. In contrast, the single SAD study did not find a relationship between these parameters. For studies involving mood disorders (n = 25), 12 studies (48%) reported a positive relationship between psychoactive effects and therapeutic response. Others 12 studies (48%) identified a null relationship, and one study (4%) found a significant negative association. Although we have found a larger association than previous studies between ketamine's psychoactive properties and its efficacy in treating a broad spectrum of psychiatric disorders, its topic remains indeterminate, mainly due to the high heterogeneity.

The association between study design and antidepressant effects in psychedelic-assisted therapy: A meta-analysis.

Different study designs of psychedelic trials may impact the blinding and expectance, leading to biased treatment effects. This study aimed to examine the association between antidepressant efficacy and study designs in psychedelic trials. Six databases were systematically searched. Eligible trials were required to investigate the efficacy of psychedelics (psilocybin, lysergic acid diethylamide [LSD], 3,4-Methylenedioxymethamphetamine [MDMA], and ayahuasca) in adult patients with depressive symptoms. We only considered oral psychedelic-assisted therapy without concomitant use of antidepressants. The primary outcome was the change in depressive symptoms. There were five study designs of psychedelic trials, including non-active-drug-as-placebo, active-drug-as-placebo, waitlist-as-control, fixed-order, and pre-post designs. In non-active-drug -as-placebo design, psilocybin (k = 4, Hedges' g [g] = 0.87, 95 % confidence intervals[CIs] = 0.58 to 1.16) and MDMA (k = 2, g = 0.65, 95%CIs = 0.26 to 1.05) were associated with large and medium effect sizes, respectively. In active-drug-as-placebo design, both psilocybin (k = 2, g = 0.71, 95%CIs = -0.01 to 1.43) and MDMA (k = 3, g = 0.53, 95%CIs = -0.23 to 1.28) were not statistically significant. In pre-post single-arm (k = 3, g = 2.51, 95%CIs = 1.00 to 4.02) and waitlist-as-control (k = 1, g = 2.88, 95%CIs = 1.75 to 4.00) designs, psilocybin showed a large effect size of antidepressant effect. Ayahuasca also showed a large effect size in both pre-post (k = 2, g = 1.88, 95%CIs = 1.18 to 2.57) and non-active-drug-as-placebo (k = 1, g = 1.60, 95%CIs = 0.84 to 2.36) designs. LSD was associated with a significant antidepressant effect only in non-active-drug-as-placebo design (k = 1, g = 1.49, 95%CIs = 0.80 to 2.17) but not in active-drug-as-placebo design (k = 1, g = 0.44, 95%CIs = -0.90 to 1.78). The antidepressant effects of psychedelics may be overestimated in studies with pre-post single-arm, non-active-drugs-as placebo, and waitlist-control designs. Restricted sample size, difficulty with establishing blinding for participants, and over expectancy limit the estimation of the antidepressant effect of psychedelic-assisted therapy.

[Epigenetic changes in alcohol addiction and therapeutic perspectives]. / Modifications épigénétiques dans l'addiction à l'alcool et perspectives thérapeutiques.

Alcohol consumption is a major public health issue. Patients with Alcohol Use Disorder (AUD) can benefit from five treatments that preferentially target membrane receptors, and whose efficacy is generally modest. However, a large body of experimental evidence points to an important role for epigenetics in the effects of alcohol consumption, and epidrugs that modify the epigenome offer an interesting alternative to current therapeutic options. This article reviews the most striking experimental evidence obtained at different ages in animal models, before comparing it with data obtained in humans and concluding on the relevance of using epidrugs. Finally, a new therapeutic option is suggested between psychedelics, recent molecules of interest, and epigenetic factors in alcohol intake.

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.

Moving psychedelic-assisted therapies from promising research into routine clinical practice: Lessons from the field of implementation science.

Psychedelics (e.g., 3,4-Methylenedioxymethamphetamine [MDMA], lysergic acid diethylamide [LSD], psilocybin) are molecules that have the potential to produce rapid therapeutic effects when paired with psychotherapy. Randomized clinical trials of psychedelic-assisted psychotherapy (PAT) have shown promising results for post-traumatic stress disorder (PTSD), depression, and substance use disorders. The U.S. Food and Drug Administration has acknowledged the promise of PAT, signaling potential approval of psilocybin-assisted therapy for depression by 2026. Given this timeline, implementation scientists must engage with PAT researchers, policymakers, and practitioners to think critically about bringing these promising new treatments into routine practice settings while maintaining quality and safety. This commentary aims to initiate a dialogue between implementation scientists and PAT researchers and practitioners on addressing these questions with a lens toward equity. Specifically, we discuss how the field of implementation science can support PAT stakeholders to accelerate the translational process from research into practice, focusing specifically on safety-net settings (i.e., Federally Qualified Health Centers and Veterans Affairs health systems) that serve historically marginalized populations. We use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework to illustrate five critical areas where implementation science can help move PAT from research into real-world practice. For each RE-AIM dimension, we highlight ways the field of implementation science can contribute tools (e.g., implementation strategies), methodologies (e.g., pragmatic hybrid implementation-effectiveness trials), and approaches (community-based participatory research) for establishing the safety, effectiveness, and accessibility of PAT for historically underserved communities.

Clinical trials of psychedelic-assisted therapy (PAT) have shown promising safety and efficacy results for treating a number of mental health conditions, including post-traumatic stress disorder, depression, anxiety/depression associated with life-threatening illnesses (e.g. cancer), eating disorders, and alcohol and tobacco use disorders. PAT researchers and practitioners must think critically about how to best bring these promising treatments into routine practice settings that are outside the confines of randomized clinical trials. This commentary aims to initiate an ongoing dialogue on how the field of implementation science can contribute tools, methodologies, and approaches to help move PAT from research into practice for historically underserved communities. We use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to illustrate five critical areas where PAT can help move from randomized control trials into practice. Throughout all the considerations we pose, we highlight how an equity lens is necessary to acknowledge and address harms caused to historically marginalized communities by policies like the "War on Drugs" and advocate that those most in need of PAT receive it first at safety-net health settings like Federally Qualified Health Centers and the Veterans Affairs.

Rapid and sustained reduction of treatment-resistant PTSD symptoms after intravenous ketamine in a real-world, psychedelic paradigm.

BACKGROUND: Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments-including preparatory, integration, sensory immersion, and psychotherapy sessions-could decrease PTSD symptoms meaningfully. METHODS: A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials. RESULTS: Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients' final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms. CONCLUSION: Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine's potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule's cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.

Psychedelic research, assisted therapy and the role of the anaesthetist: A review and insights for experimental and clinical practices.

Recent years have witnessed an unprecedented increase in the search for the use of psychedelics in improving physical and mental health. Anaesthesia has evolved since very early times, born from the need to eliminate pain and reduce suffering and there are reports of the use of anaesthetics to achieve mystical states since the nineteenth century. Nowadays, the renaissance of psychedelics in anaesthesia has been inspired by their potential in the treatment of chronic pain syndromes, palliative care and in the emergency department and pre-hospital care with the administration of psychedelics in cases of ischaemia, given their potential in neuroprotection. Although there are already some published protocols for the administration of psychedelics in patients with mental illness, little has been addressed concerning non-mental medical applications. In this sense, in patients with multiple comorbidities, functional limitations and polymedicated, the anaesthetist may play a fundamental role, not only in clinical practice, but also in translational research. This article focuses on the description of psychedelics, with a particular focus on dimethyltryptamine (DMT) and ayahuasca pharmacology, effects, safety and toxicity. A detailed description of the role of the anaesthetist in clinical and experimental research is provided, from participant's screening to preparation and dosing session, expected adverse effects and how to manage them, based on the protocol and standard procedures of a current study with neuroimaging during the psychedelic experience. Specific considerations regarding the management of psychedelic toxicity are also provided as well as future directions for safe psychedelic use in clinical practice.

Neuroprotective effects of psilocybin in a rat model of stroke.

BACKGROUND: Psilocybin is a psychedelic 5HT2A receptor agonist found in "magic mushrooms". Recent studies have indicated that 5HT2A agonists, such as dimethyltryptamine, given before middle cerebral artery occlusion (MCAo), improve staircase behavior, increased BDNF expression, and reduce brain infarction in stroke rats. The objective of this study is to determine the protective effect of psilocybin in cellular and animal models of stroke. METHODS: Adult male and timed-pregnant Sprague-Dawley rats were used for this study. The neural protective effects of psilocybin were determined in primary rat cortical neurons and adult rats. Rats were subjected to a 60-min middle cerebral artery occlusion. Brain tissues were collected for histological and qRTPCR analysis. RESULTS: Psilocybin reduced glutamate-mediated neuronal loss in rat primary cortical neuronal cultures. Psilocybin-mediated protection in culture was antagonized by the BDNF inhibitor ANA12. Pretreatment with psilocybin reduced brain infarction and neurological deficits in stroke rats. Early post-treatment with psilocybin improved locomotor behavior, upregulated the expression of MAP2 and synaptophysin, and down-regulated the expression of IBA1 in the stroke brain. ANA12 significantly attenuated psilocybin-mediated reduction in brain infarction and improvements in locomotor behavior. CONCLUSIONS: Psilocybin reduced brain infarction and improved locomotor behavior in stroke rats; the protective mechanisms involve regulating BDNF expression. Our data support a novel therapeutic approach of psilocybin in stroke.

Healing with Ayahuasca the Plant Teacher: Psychedelic Metaphoricity and Polyontologies.

Shamans, neo-shamans, atheists, and others describe gaining special knowledge from drinking ayahuasca, supporting the cross-cultural idea of ayahuasca as a plant teacher. While secular enthusiasts interpret this metaphorically, animists and others take it literally. This article examines ontological collisions at a healing retreat in the Peruvian Amazon, considering Shipibo shamans and their international clients. It explores how embodied experiences, such as purging and visions, inform both literal and metaphorical views of healing and illness. By addressing incommensurable ontologies, the article highlights how a polyontological framework approaches ontological collision without necessarily privileging specific ways of knowing.

Acute Psychedelic Reactions, Post-Acute Changes in Dysfunctional Attitudes, and Psychedelic-Associated Changes in Wellbeing.

Dysfunctional attitudes - a cornerstone to cognitive psychotherapy - vary with both psychological and pharmacological interventions. Post-acute changes in these cognitions appear to covary with the acute reactions to psychedelics that often precede improved outcomes. An examination of post-acute changes in dysfunctional attitudes could support targeting them in psychedelic-assisted therapy. Screened participants (N = 400+) reported the acute, subjective experiences associated with their most significant psychedelic response as well as post-acute changes in dysfunctional attitudes and subsequent alterations in wellbeing. Dysfunctional attitudes, emotional breakthroughs, and challenging experiences accounted for significant, unique variance in wellbeing. The effects of dysfunctional attitudes generally exceeded those of acute reactions. Comparisons among those acute responses revealed that the effect of emotional breakthroughs exceeded challenging experiences, which exceeded mystical experiences. Nevertheless, the indirect effects through post-acute changes in dysfunctional attitudes did not account for all the impact of acute effects nor interact with them. These results emphasize the import of both acute and post-acute reactions, suggesting that strategies for optimizing each might maximize outcomes for psychedelic-assisted interventions. Furthermore, standard cognitive interventions that alter these cognitions could combine with psychedelics in straightforward ways. The results also support the use of multiple multivariate approaches to address the relative importance of multicollinear predictors.

Examining differences in the effects and contexts of naturalistic psilocybin use for White participants vs. Participants of Color: A longitudinal online survey study.

BACKGROUND: Psilocybin (a psychoactive compound found in "magic mushrooms" or "shrooms") has been gaining increased attention in research and popular culture as a number of clinical and observational studies have demonstrated that it may have potential for improving mental wellbeing. Relatedly, there has been a substantial uptick in naturalistic (e.g., real-world, non-clinical) psilocybin use in the United States. While a number of longitudinal studies have demonstrated that naturalistic psilocybin use is linked to positive mental health outcomes on average, few studies have examined how the effects of psilocybin and contexts for psilocybin use may differ for White populations compared to Populations of Color. OBJECTIVE: To examine differences in health outcomes, subjective effects, and contexts of naturalistic psilocybin use in White participants compared to Participants of Color. METHODS: This study used data from a large, online longitudinal study of individuals who planned to engage in naturalistic psilocybin use (N = 2833). We used mixed-effects models to assess whether race/ethnicity (White vs. Participant of Color) moderated associations between time (Time 2 [initial assessment point for longitudinal measures], Time 5 [2-4 weeks post-psilocybin experience, and Time 6 [2-3 months post-experience]) and outcomes related to mental health (depression, anxiety, spiritual wellbeing, cognitive flexibility, emotion regulation [expressive suppression + cognitive reappraisal]). We also used exploratory chi-squared tests to examine differences in contexts for psilocybin use as well as differences in subjective effects related to the psilocybin experience. RESULTS: Race/ethnicity moderated the associations between time for predicting spiritual wellbeing (beta = -1.8; 95 % CI [-3.4, -0.17]; p < 0.05), cognitive flexibility (beta = -1.5 [-2.7, -0.26]; p < 0.05), and emotion regulation - expressive suppression (beta = 0.25 [0.06, 0.44]; p < 0.05) at Time 6 (but not Time 5). Additionally, Participants of Color reported minor differences in subjective effects and context for use compared to White participants (e.g., more likely to have set an intention prior to use, report time speeding up during the experience, etc.). We found reductions in anxiety and depression for both Participants of Color and White participants, and our moderation tests for these outcomes were not significant. CONCLUSION: Race/ethnicity impacts the associations between psilocybin use and various markers of mental wellbeing. Future longitudinal studies and experimental studies with larger samples of color can further elucidate the preliminary findings from this study.

Substrate recognition by the 4-hydroxytryptamine kinase PsiK in psilocybin biosynthesis.

Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l-tryptophan involves four strictly sequential modifications. The third of these, ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure-based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties.

Chemistry/structural biology of psychedelic drugs and their receptor(s).

This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules. With a focus on the 5-HT2A receptor subtype, a G-protein coupled receptor known to be the primary target of psychedelics, we refer to several X-ray and cryoEM structures, with a variety of ligands bound, to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions.

A Cross-Sectional Survey Investigating Maori and Non-Maori Cancer Patients' Views on Psychedelic-Assisted Therapy in Aotearoa New Zealand.

People with cancer experience higher rates of psychological dysfunction than the general population, with extreme inequity among indigenous people. Psychedelic-assisted therapy (PAT) is a reemerging area with promising evidence as a treatment for mental health difficulties. The current study aimed to investigate the perceptions of PAT in indigenous (Maori) and non-indigenous cancer patients in Aotearoa, New Zealand. Eighty-five cancer patients (Maori n = 32, non-Maori n = 53) completed a brief anonymous survey assessing demographics, psychological factors, and awareness and perceptions of PAT. Participants were recruited online (via social media and cancer support e-mail lists) and in person at Auckland City Hospital. Maori had significantly poorer psychological well-being than non-Maori. All participants had low awareness of this novel treatment and held largely neutral attitudes. Regression analyses revealed that predictors of more favorable attitudes toward PAT included greater awareness of psychedelics, advanced cancer stage, younger age, poorer holistic well-being, greater demoralization, and prioritizing treatment effectiveness over possible risks and uncertainty. The current study provides a foundational step in exploring perceptions toward PAT in indigenous and non-indigenous groups. These results have the potential to shape future research trials investigating PAT and further highlight the importance of indigenous involvement in the psychedelic research space.

Efficacy, Safety, and Tolerability of Psychedelics in Treatment-Resistant Depression (TRD).

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.

The Epidemiology of Psychedelic Use Among United States Military Veterans.

We sought to identify patterns of psychedelic use among United States military veterans, compare demographic variables and perspectives of those who did and did not report use, and characterize benefits and adverse outcomes associated with use. Respondents (N = 426) were recruited to complete an online cross-sectional survey. Approximately one-half (51%) reported using psychedelics. Most did so for healing/treatment (70%) and/or spiritual purposes (48%), and most (85%) reported benefiting from use. Those who used psychedelics reported they would be more likely to use VA services (p < .001, d = 0.64) and to return to the VA for care (p < .001, d = 0.79) if psychedelic therapy was offered. Almost two-thirds (59%) reported adverse outcomes associated with use. Equivalent proportions rated their psychedelic experiences as beneficial among those who did (89%) and did not (81%) report adverse outcomes. Fewer adverse outcomes were associated with being older, using psilocybin, feeling prepared and confident in the reasons for use, being in a comfortable setting, and being able to "trust, let go, and be open" (Rc = 0.77; p < .001). Psychedelics may offer benefits but may also lead to adverse outcomes without proper preparation and support. Future research should examine the utility of psychedelic-based approaches for veteran mental health care.