Visual mismatch negativity in Parkinson's psychosis and potential for testing treatment mechanisms.

Psychosis and visual hallucinations are a prevalent non-motor symptom of Parkinson's disease, negatively affecting patients' quality of life and constituting a greater risk for dementia. Understanding neural mechanisms associated to these symptoms is instrumental for treatment development. The mismatch negativity is an event-related potential evoked by a violation in a sequence of sensory events. It is widely considered an index of sensory change-detection. Reduced mismatch negativity response is one of the most replicated results in schizophrenia and has been suggested to be a superior psychosis marker. To understand whether this event-related potential component could be a similarly robust marker for Parkinson's psychosis, we used electroencephalography with a change-detection task to study the mismatch negativity in the visual modality in 20 participants with Parkinson's and visual hallucinations and 18 matched Parkinson's participants without hallucinations. We find that visual mismatch negativity is clearly present in participants with Parkinson's disease without hallucinations at both parieto-occipital and frontal sites, whereas participants with Parkinson's and visual hallucinations show reduced or no differences in the two waveforms, confirming the sensitivity of mismatch negativity to psychosis, even within the same diagnostic group. We also explored the relationship between hallucination severity and visual mismatch negativity amplitude, finding a negative correlation between visual hallucinations severity scores and visual mismatch negativity amplitude at a central frontal and a parieto-occipital electrodes, whereby the more severe or complex (illusions, formed visual hallucinations) the symptoms the smaller the amplitude. We have also tested the potential role of the serotonergic 5-HT2A cascade in visual hallucinations in Parkinson's with these symptoms, following the receptor trafficking hypothesis. We did so with a pilot study in healthy controls (N = 18) providing support for the role of the Gi/o-dependent pathway in the psychedelic effect and a case series in participants with Parkinson's and visual hallucinations (N = 5) using a double-blind crossover design. Positive results on psychosis scores and mismatch amplitude add further to the potential role of serotonergic modulation of visual hallucinations in Parkinson's disease.

Autonomic nervous system activity correlates with peak experiences induced by DMT and predicts increases in well-being.

BACKGROUND: Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called "peak experiences," characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extent changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). METHODS: We derived measures of SNS and PNS activity from the electrocardiograms of 17 participants (11 males, mean age = 33.8 years, SD = 8.3) while they received either DMT or placebo. RESULTS: Results show that the joint influence of SNS and PNS ("sympathovagal coactivation") over cardiac activity was positively related to participants' ratings of "Spiritual Experience" and "Insightfulness" during the DMT experience, while also being related to improved well-being scores 2 weeks after the session. In addition, we found that the state of balance between the two ANS branches ("sympathovagal balance") before DMT injection predicted scores of "Insightfulness" during the DMT experience, as well as subsequent sympathovagal coactivation. CONCLUSION: These findings demonstrate the involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic therapy.

Psychedelics: From Cave Art to 21st-Century Medicine for Addiction.

BACKGROUND: Psychedelic substance use in ritualistic and ceremonial settings dates back as early as 8,500 BCE. Only in recent years, from the mid-20th century, we have seen the re-emergence of psychedelics in a therapeutic setting and more specifically for the treatment of addiction. This article aims to review research over the past 40 years using classic (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], mescaline) and atypical (ketamine, ibogaine, 5-MeO-DMT, 3,4-methylenedioxymethamphetamine) psychedelics for the treatment of addiction. SUMMARY: We will start with an overview of the pharmacology and physiological and psychological properties of psychedelic substances from pre-clinical and clinical research. We will then provide an overview of evidence gathered by studies conducted in controlled research environments and naturalistic and ceremonial settings, while we identify the proposed therapeutic mechanisms of each psychedelic substance. KEY MESSAGES: Classic and atypical psychedelics show promise as therapeutic alternatives for the treatment of addiction, through the improvement of psychological and physiological symptoms of dependence. A more comprehensive understanding of the ancient and present-day knowledge of the therapeutic potential of psychedelics can facilitate hope for psychedelic therapeutics in the treatment of addiction, especially for individuals who have failed other conventional treatment methods.

Exploratory study of associations between monetary reward anticipation brain responses and mu-opioid signalling in alcohol dependence, gambling disorder and healthy controls.

Alcohol dependence (AD) and gambling disorder (GD) are common addiction disorders with significant physical and mental health consequences. AD and GD are associated with dysregulated responses to reward which could be due to a common mechanism of dysregulated endogenous opioid signalling. We explored associations between reward anticipation responses, using the Monetary Incentive Delay (MID) functional magnetic resonance imaging (fMRI) task, and mu-opioid receptor (MOR) availability and endogenous opioid release capacity using [11C]carfentanil positron emission tomography (PET), in 13 AD, 15 GD and 14 heathy control (HC) participants. We also examined differences in MID task reward anticipation responses between AD, GD and HC participants. These were secondary exploratory analysis of data collected to examine differences in MOR PET in addiction. We did not find significant differences in MID win > neutral anticipation BOLD responses compared between participant groups in a priori ROIs (ventral striatum, putamen, caudate) or whole brain analyses. We found no significant correlations between MID win > neutral anticipation BOLD responses and [11C]carfentanil PET measures, except for limited negative correlations between putamen MOR availability and MID win > neutral anticipation BOLD response in AD participants. Previous research has suggested a limited role of endogenous opioid signalling on MID task reward anticipation responses in AD and HCs as these responses are not modulated by opioid receptor blockade and this may explain our lack of significant correlations in HC and AD or GD participants. Our results, particularly the lack of differences in MID win > neutral anticipation BOLD responses across participants groups, may be limited due to only including AD or GD participants who are abstinent or in active treatment.

Interrupting the Psychedelic Experience Through Contextual Manipulation to Study Experience Efficacy.

This quality improvement study investigates the association of interruptions during psychedelic therapy with ratings of intensity of experience.

Study protocol for "Psilocybin in patients with fibromyalgia: brain biomarkers of action".

Background: Chronic pain is a leading cause of disability worldwide. Fibromyalgia is a particularly debilitating form of widespread chronic pain. Fibromyalgia remains poorly understood, and treatment options are limited or moderately effective at best. Here, we present a protocol for a mechanistic study investigating the effects of psychedelic-assisted-therapy in a fibromyalgia population. The principal focus of this trial is the central mechanism(s) of psilocybin-therapy i.e., in the brain and on associated mental schemata, primarily captured by electroencephalography (EEG) recordings of the acute psychedelic state, plus pre and post Magnetic Resonance Imaging (MRI). Methods: Twenty participants with fibromyalgia will complete 8 study visits over 8 weeks. This will include two dosing sessions where participants will receive psilocybin at least once, with doses varying up to 25mg. Our primary outcomes are 1) Lempel-Ziv complexity (LZc) recorded acutely using EEG, and the 2) the (Brief Experiential Avoidance Questionnaire (BEAQ) measured at baseline and primary endpoint. Secondary outcomes will aim to capture broad aspects of the pain experience and related features through neuroimaging, self-report measures, behavioural paradigms, and qualitative interviews. Pain Symptomatology will be measured using the Brief Pain Inventory Interference Subscale (BPI-IS), physical and mental health-related function will be measured using the 36-Item Short Form Health Survey (SF-36). Further neurobiological investigations will include functional MRI (fMRI) and diffusion tensor imaging (changes from baseline to primary endpoint), and acute changes in pre- vs post-acute spontaneous brain activity - plus event-related potential functional plasticity markers, captured via EEG. Discussion: The results of this study will provide valuable insight into the brain mechanisms involved in the action of psilocybin-therapy for fibromyalgia with potential implications for the therapeutic action of psychedelic-therapy more broadly. It will also deliver essential data to inform the design of a potential subsequent RCT.

Prescribed Medical Cannabis Use Among Older Individuals: Patient Characteristics and Improvements in Well-Being: Findings from T21.

BACKGROUND: Previous research has suggested that the use of cannabis-based medicinal products is increasing most rapidly among older aged individuals (65+ years). Despite this, little is known about the characteristics of older people using cannabis-based medicinal products and their effectiveness. OBJECTIVES: We aimed to document the characteristics, outcomes and prescribing patterns of individuals aged 65+ years receiving prescribed cannabis compared to younger individuals receiving prescribed cannabis. METHODS: Data from T21, an observational study of patients seeking treatment with medicinal cannabinoids, including self-report ratings of quality of life (assessed via the EQ-5D-5L), general health (assessed via the visual analogue scale of the EQ-5D-5L), mood (assessed via the Patient Health Questionnaire-9) and sleep (assessed using four items derived from the Pittsburgh Sleep Quality Index) were available at treatment entry [n = 4228; 198 (4.7%) 65+ years] and at a 3-month follow-up [n = 2455; 98 (4.2%) = 65+ years]. RESULTS: Relative to younger individuals, those aged over 64 years were more likely to be female (52.5% vs 47.0%; p < 0.001), more likely to report pain as their primary condition (76.3% vs 45.6%; p < 0.001) and less likely to report current daily use (20.2% vs 60.3%, p < 0.001). They received fewer cannabis-based medicinal products (mean = 1.4 vs 2.1; F(1,2199) = 32.3, p < 0.001) and were more likely to receive a prescription for a cannabidiol dominant oil (17.5% vs 5.7%; p < 0.001) and less likely to receive a prescription for delta-9-tetrahydrocannabinol dominant flower (32.5% vs 75.2%; p < 0.001). There were significant improvements across all measures of well-being (p < 0.001), but the extent of improvements in sleep were more marked in younger individuals (p < 0.001). CONCLUSIONS: There are important differences between individuals aged 65+ years and younger individuals receiving cannabis-based medicinal products. Older aged individuals experience considerable improvement in health and well-being when prescribed cannabis-based medicinal products.

The flattening of spacetime hierarchy of the N,N-dimethyltryptamine brain state is characterized by harmonic decomposition of spacetime (HADES) framework.

The human brain is a complex system, whose activity exhibits flexible and continuous reorganization across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. Here, we investigate healthy participants taking the serotonergic psychedelic N,N-dimethyltryptamine (DMT) with the Harmonic Decomposition of Spacetime (HADES) framework that can characterize how different harmonic modes defined in space are expressed over time. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the leading hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES' dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

Is it now time to prepare psychiatry for a psychedelic future?

Australia has just rescheduled two drugs controlled under the United Nations Psychotropic Drug Conventions, psilocybin and MDMA, as treatments for treatment-resistant depression and post-traumatic stress disorder respectively. This feature explores the reasons for these developments, the opportunities and challenges they provide to psychiatry communities and how along with health systems these communities might respond to these developments.

Brain dynamics predictive of response to psilocybin for treatment-resistant depression.

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression.

BACKGROUND: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

Medicinal cannabis for treating post-traumatic stress disorder and comorbid depression: real-world evidence.

BACKGROUND: Cannabis-based medicinal products (CBMPs) are increasingly being used to treat post-traumatic stress disorder (PTSD), despite limited evidence of their efficacy. PTSD is often comorbid with major depression, and little is known about whether comorbid depression alters the effectiveness of CBMPs. AIMS: To document the prevalence of depression among individuals seeking CBMPs to treat PTSD and to examine whether the effectiveness of CBMPs varies by depression status. METHOD: Data were available for 238 people with PTSD seeking CBMP treatment (5.9% of the treatment-seeking sample) and 3-month follow-up data were available for 116 of these. Self-reported PTSD symptoms were assessed at treatment entry and at 3-month follow-up using the PTSD Checklist - Civilian Version (PCL-C). The probable presence of comorbid depression at treatment entry was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Additional data included sociodemographic characteristics and self-reported quality of life. RESULTS: In total, 77% met screening criteria for depression, which was associated with higher levels of PTSD symptomatology (mean 67.8 v. 48.4, F(1,236) = 118.5, P < 0.001) and poorer general health, quality of life and sleep. PTSD symptomatology reduced substantially 3 months after commencing treatment (mean 58.0 v. 47.0, F(1,112) = 14.5, P < 0.001), with a significant interaction (F(1,112) = 6.2, P < 0.05) indicating greater improvement in those with depression (mean difference 15.3) than in those without (mean difference 7). CONCLUSIONS: Depression is common among individuals seeking CBMPs to treat PTSD and is associated with greater symptom severity and poorer quality of life. Effectiveness of CBMPs for treating PTSD does not appear to be impaired in people with comorbid depression.

A perspective on psychedelics as treatments for addictions: Past, Present, and Future.

This Perspectives piece gives a brief overview on the last 70 years of psychedelic research in relation to the treatment of mental illness with a particular focus on addictions. We briefly precis the work in the 19650s/60s that started following the discovery of LSD. Then we overview research developments over the past twenty years driven by emerging neuroscience on these agents, the rise of MDMA use in psychotherapy and the emergence of ketamine as a treatment for mental illnesses. We then briefly outline new research on the brain mechanisms of these therapeutic effects. Finally the current status of research and future challenges in the field are reviewed.

AUD in perspective.

Alcohol is a major cause of pre-mature death and individual suffering worldwide, and the importance of diagnosing and treating AUD cannot be overstated. Given the global burden and the high attributable factor of alcohol in a vast number of diseases, the need for additional interventions and the development of new medicines is considered a priority by the World Health Organization (WHO). As of today, AUD is severely under-treated with a treatment gap nearing 90%, strikingly higher than that for other psychiatric disorders. Patients often seek treatment late in the progress of the disease and even among those who seek treatment only a minority receive medication, mirroring the still-prevailing stigma of the disease, and a lack of access to effective treatments, as well as a reluctance to total abstinence. To increase adherence, treatment goals should focus not only on maintaining abstinence, but also on harm reduction and psychosocial functioning. A personalised approach to AUD treatment, with a holistic view, and tailored therapy has the potential to improve AUD treatment outcomes by targeting the heterogeneity in genetics and pathophysiology, as well as reason for, and reaction to drinking. Also, the psychiatric co-morbidity rates are high in AUD and dual diagnosis can worsen symptoms and influence treatment response and should be considered in the treatment strategies.

Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives.

The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to 3 million deaths in 2016 while also being responsible for 5·1% of the global burden of disease and injury. The total elimination of alcohol consumption, which has been long imbedded in human culture and society, is not practical and prohibition policies have proved historically ineffective. However, valuable strategies to reduce alcohol harms are already available and improved alternative approaches are currently being developed. Here, we will review and discuss recent advances on two main types of approaches, that is nutritional interventions and functional alcohol alternatives.

Psychedelics and sexual functioning: a mixed-methods study.

Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with one's partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.

Effects of DMT on mental health outcomes in healthy volunteers.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybin's acute effects (4-6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1-2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via 'Oceanic Boundlessness'). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

Predicting the outcome of psilocybin treatment for depression from baseline fMRI functional connectivity.

BACKGROUND: Psilocybin is a serotonergic psychedelic drug under assessment as a potential therapy for treatment-resistant and major depression. Heterogeneous treatment responses raise interest in predicting the outcome from baseline data. METHODS: A machine learning pipeline was implemented to investigate baseline resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI) as a predictor of symptom severity in psilocybin monotherapy for treatment-resistant depression (16 patients administered two 5 mg capsules followed by 25 mg, separated by one week). Generalizability was tested in a sample of 22 patients who participated in a psilocybin vs. escitalopram trial for moderate-to-severe major depression (two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo vs. two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram). The analysis was repeated using both samples combined. RESULTS: Functional connectivity of visual, default mode and executive networks predicted early symptom improvement, while the salience network predicted responders up to 24 weeks after treatment (accuracy≈0.9). Generalization performance was borderline significant. Consistent results were obtained from the combined sample analysis. Fronto-occipital and fronto-temporal coupling predicted early and late symptom reduction, respectively. LIMITATIONS: The number of participants and differences between the two datasets limit the generalizability of the findings, while the lack of a placebo arm limits their specificity. CONCLUSIONS: Baseline neurophysiological measurements can predict the outcome of psilocybin treatment for depression. Future research based on larger datasets should strive to assess the generalizability of these predictions.

Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations.

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity.