Qualitative Content Analysis of Expectations in participants with depression about to begin LSD microdosing treatment: Identifying the need for psychedelic expectancy measures.

Expectations can impact antidepressant treatment and psychedelic therapy, often enhance placebo effects and influence outcomes. However, research in this context is lacking. Our study explored the expectations of participants with major depressive disorder (MDD) before microdosing lysergic acid diethylamide (LSD) in an open-label trial.

LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics.

Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity.

The role of GABA, glutamate, and Glx levels in treatment of major depressive disorder: A systematic review and meta-analysis.

This systematic review and meta-analysis aims to explore a possible role of gamma-aminobutyric acid (GABA) and glutamate, as measured by Magnetic Resonance Spectroscopy (MRS), in the treatment outcomes of people with Major Depressive Disorder (MDD). Despite the prevalence of MDD and various treatment modalities, the neurobiological mechanisms of each remain poorly understood. We synthesised data from 41 longitudinal studies comprising 918 individuals with MDD, spanning four primary treatment modalities: selective serotonin reuptake inhibitors (SSRIs), ketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT).

Mapping Neuroinflammation With Diffusion-Weighted Magnetic Resonance Imaging: A Randomized Crossover Study.

Background: The pathophysiology of neuroinflammation in psychiatric conditions remains poorly understood, highlighting the need for noninvasive tools that can measure neuroinflammation in vivo. We explored advanced diffusion-weighted magnetic resonance imaging (MRI) techniques for detection of low-level neuroinflammation induced by typhoid vaccine, with potential applications to psychiatric disorders.

Methods: Twenty healthy volunteers (10 males; median age 34, range 18-44 years) participated in a randomized, placebo-controlled, crossover design study.

Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.

Introduction: Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).

Methods: This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety).

The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State.

Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression.

The Effects of Neuroinflammation Induced by Typhoid Vaccine on Resting and Task-Based Electroencephalography.

Introduction: Considerable evidence suggests a pathophysiological role of neuroinflammation in psychiatric disorders. Lumbar puncture and positron emission tomography (PET) show increased levels of inflammation in psychiatric disorders. However, the invasive nature of these techniques, as well as their expense, make them undesirable for routine use in patients.

Local activity alterations in autism spectrum disorder correlate with neurotransmitter properties and ketamine induced brain changes.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition (E/I) ratio is discussed as a potential pathomechanism but in-vivo evidence of disturbed neurotransmission underlying these functional alterations remains scarce. We compared rs-fMRI local activity (LCOR) between ASD (N=405, N=395) and neurotypical controls (N=473, N=474) in two independent cohorts (ABIDE1 and ABIDE2).

Multimodal creativity assessments following acute and sustained microdosing of lysergic acid diethylamide.

Introduction: Enhanced creativity is often cited as an effect of microdosing (taking repeated low doses of a psychedelic drug). There have been recent efforts to validate the reported effects of microdosing, however creativity remains a difficult construct to quantify.

Objectives: The current study aimed to assess microdosing's effects on creativity using a multimodal battery of tests as part of a randomised controlled trial of microdosing lysergic acid diethylamide (LSD).

LSDDEP2: study protocol for a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients with major depressive disorder.

Background: Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities.

LSD increases sleep duration the night after microdosing.

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day.

Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine.

Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms-it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion.

Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial.

Background: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks.

Microdosing Psychedelics: Current Evidence From Controlled Studies.

Taking regular low doses of psychedelic drugs (microdosing) is a practice that has drawn recent scientific and media attention for its potential psychotherapeutic effects. Yet, controlled studies evaluating this practice have lagged. Here, we review recent evidence focusing on studies that were conducted with rigorous experimental control.

Effects of External Stimulation on Psychedelic State Neurodynamics.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g.

Resting-state EEG connectivity recorded before and after rTMS treatment in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy and tolerability in Major Depressive Disorder (MDD). However, the underlying mechanisms of its antidepressant effects remain unclear. This open-label study investigated electroencephalography (EEG) functional connectivity markers associated with response and the antidepressant effects of rTMS.

Overcoming blinding confounds in psychedelic randomized controlled trials using biomarker driven causal mediation analysis.

Introduction: There is great interest in the use of psychedelic-assisted therapies to treat a range of mental health conditions and initial randomized controlled trials (RCTs) have generated positive results. However, the effect sizes reported in psychedelic RCTs are likely inflated due to expectancy effects due to the de-blinding of both participants and study personnel to treatment allocation caused by the distinctive psychoactive effects of psychedelic drugs.

Areas Covered: An introduction to causal inference for RCTs, the underlying assumptions, and potential confounders along with graphical illustrations is provided.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1).

Background: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice.

Detection of Neuroinflammation Induced by Typhoid Vaccine Using Quantitative Magnetization Transfer MR: A Randomized Crossover Study.

Background: The role of neuroinflammation in psychiatric disorders is not well-elucidated. A noninvasive technique sensitive to low-level neuroinflammation may improve understanding of the pathophysiology of these conditions.

Purpose: To test the ability of quantitative magnetization transfer (QMT) MR at 3 T for detection of low-level neuroinflammation induced by typhoid vaccine within a clinically reasonable scan time.

Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials.

What happens when an emerging programme of medical research overlaps with a surging social movement? In this article we draw on the anthropological term 'chemosociality' to describe forms of sociality born of shared chemical exposure. Psychedelic administration in the context of recent clinical trials appears to have been particularly chemosocial in nature. We argue that one consequence is that psychedelic-assisted therapy (PAT) clinical research trials tend to breach key assumptions underlying the logic of causal inference used to establish efficacy.

The New Zealand drug harms ranking study: A multi-criteria decision analysis.

Aims: The harms arising from psychoactive drug use are complex, and harm reduction strategies should be informed by a detailed understanding of the extent and nature of that harm. Drug harm is also context specific, and so any comprehensive assessment of drug harm should be relevant to the characteristics of the population in question. This study aimed to evaluate and rank drug harms within Aotearoa New Zealand using a multi-criteria decision analysis (MCDA) framework, and to separately consider harm within the total population, and among youth.

Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives.

Introduction: The combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations.

Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

Background: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity.

Methods: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 μg LSD or an inactive placebo every 3 days for 6 weeks.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls.

The perceptions of cancer health-care practitioners in New Zealand and the USA toward psychedelic-assisted therapy with cancer patients: A cross-sectional survey.

Objectives: A resurgence of research investigating the administration of psychedelic compounds alongside psychotherapy suggests that this treatment is a promising intervention for anxiety, depression, and existential distress in people with cancer. However, psychedelic treatment that induces a mind-altering experience potentially poses barriers to vulnerable cancer patients, and health-care practitioners may have concerns about referring their patients to trials investigating this approach. The aim of the current study was to investigate the perceptions of cancer health-care practitioners based in New Zealand and the USA related to psychedelic-assisted therapy.