This pilot randomized clinical trial (n=30) assessed the efficacy of a single subanesthetic dose of esketamine (14mg/70kg) in enhancing the effect of oral antidepressants for patients with fluctuating responses to treatment in major depressive disorder (MDD). Participants were adults with MDD experiencing fluctuating symptoms despite prior symptom relief and stabilization. The study found that response rates at 2 weeks were significantly higher in the esketamine group (66.7%) compared to the midazolam control group (6.7%), with a more substantial reduction in depression severity (MADRS score) in the esketamine group.
This retrospective online survey (n=160) investigates the impact of naturalistic psychedelic experiences on alcohol use (AUD) and related measures. The results indicate a significant reduction in the mean number of drinking days per week and AUDIT scores after the psychedelic experience. Subjects who quit or reduced drinking had a more severe AUD and lower psychological flexibility before the psychedelic session. The study suggests that positive health outcomes, including reduced alcohol use and dependency, may be associated with the intensity of the mystical experience and an increase in psychological flexibility.
This open-label within-subject study (n=10) compared the oral administration of a capsule (containing DMT and harmine) with combined intranasal administration of an oromucosal harmine tablet and an intranasal DMT spray at two doses. The research aimed to improve the pharmacokinetics and tolerability profiles of ayahuasca-analogue formulations. Results indicate that the combined buccal/intranasal administration substantially attenuated common side effects and yielded significantly improved pharmacokinetic profiles. This suggests it may be an innovative approach for the safe and patient-oriented administration of DMT/harmine for treating affective disorders.
This systematic review of 52 studies (n=7102) investigates drug-drug interactions between classic psychedelics (LSD, psilocybin, mescaline, DMT, 5-MeO-DMT, and ayahuasca) and various drugs, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, and recreational drugs. The findings reveal diverse interactions, ranging from attenuated to potentiated effects, with a few cases reporting no changes. Despite a lack of serious adverse events in most studies, the review emphasizes the need for a comprehensive understanding of potential interactions and explores molecular pathways underlying observed effects.
This cross-sectional survey (n=517) assessed the psychometric properties of the Spiritual Well-Being Scale (SWBS) concerning existential well-being (EWB) and religious well-being (RWB). The study found that the RWB factor exhibited superior psychometric indices for validity, group discrimination, and reliability, showing a U-shaped pattern in the association between psychedelics and spiritual well-being, where non-users and frequent users had higher RWB and EWB indices than occasional users.
This cross-sectional survey (n=841) of Norwegian adults who had memorable experiences with classic psychedelic substances reveals that the primary intentions for use were recreational (46.1%) or therapeutic (42.3%). Most participants reported psilocybin as their most memorable experience, and despite the prevalence of self-perceived symptoms of mental and substance use disorders, the psychedelic experience generally led to improvements. Adverse reactions, mostly mild and short-lived, affected 4.2% for a year or more, and persisting flashbacks were reported by 2.9% of participants.
This review (2023) examines ibogaine as a potential treatment for substance use disorders (SUDs). The lack of randomized, controlled studies on its safety and efficacy and the elusive mechanisms of action have been barriers to clinical use. The review suggests that ibogaine and its metabolite, noribogaine (NOR), modulate multiple targets associated with SUDs, emphasizing a complex, multi-target approach to understanding its pharmacology.
This Phase II clinical trial (n=329) investigated the oral administration of ketamine (extended-release tablet R-107) in adults with treatment-resistant major depression (TRD). The trial demonstrated that R-107 tablets at 180mg exhibited a significant antidepressant effect compared to placebo at 13 weeks (MADRS score -6.1. The study found a dose-response relationship in relapse rates during double-blind treatment, ranging from 70.6% for placebo to 42.9% for the 180mg dose. The treatment was well-tolerated, with no notable changes in blood pressure, minimal reports of sedation, and minimal dissociation. Common adverse events included headache, dizziness, and anxiety.
This pre-print mice study explores the impact of classical psychedelic drugs on pyramidal cells in the prefrontal cortex. Contrary to previous beliefs, the study reveals that various classes of psychedelics dose-dependently decrease intrinsic excitability of pyramidal neurons. The mechanism behind this effect involves enhancing ubiquitously expressed potassium "M-current" channels, independent of serotonin 2A receptor activation. Machine-learning-based data assimilation models suggest that M-current activation, in conjunction with known mechanisms, significantly reduces intrinsic excitability and shortens working memory timespan. The findings propose that psychedelic drugs modulate brain-wide ion channels, potentially triggering homeostatic adjustments and contributing to widespread therapeutic benefits.
This review (2023) examines the interest in ibogaine's therapeutic potential for substance use disorders over three decades (1993–2022). The study identifies a linear growth of publications in the first and third decades, with academic research centers in the United States and Canada being the most productive. Major keywords shifted from cocaine, tobacco, morphine, and alcohol in the first two decades to opioids and psychedelics in the third decade, indicating evolving research trends.
This qualitative study (n=15) explores the perspectives of ayahuasca ceremony leaders, primarily from the West/Global North, on the suitability of ceremonial ayahuasca use for individuals with eating disorders (EDs). The analysis identifies categories such as screening for EDs, purging and dietary restrictions, potential risks, and complementarity with conventional ED treatment. The findings suggest the need for careful screening and extra support to ensure safe and beneficial ayahuasca ceremony experiences for individuals with EDs.
Eating Disorders - The Journal of Treatment & Prevention
This pre-print (2023) utilizes a novel Bayesian framework to assess autonomic markers, particularly heart rate dynamics, in tracking the effects of psychedelics, including LSD, DMT, psilocybin, and ketamine. The study, encompassing datasets from these drugs, reveals consistent increases in mean heart rate, high-frequency heart rate variability, and heart rate entropy during psychedelic experiences, with these effects demonstrating predictive power over various dimensions of the psychedelic experience. The findings suggest that cost-efficient autonomic measures, particularly heart rate entropy, can provide valuable insights into subjective and brain states during psychedelic experiences, opening new avenues for research in both basic and clinical neuroscience.
This perspective article (2023) discusses the ethical considerations of providing post-trial access (PTA) in psychedelic clinical trials. It highlights the unique aspects of psychedelic trials, such as the legal status of psychedelics, the researcher-participant relationship, and the extended therapeutic process, as factors supporting the case for introducing PTA. The authors also advocate for a broader focus on post-trial care beyond access and provide an overview of potential provisions for psychedelic clinical trials, emphasizing the development of infrastructure for the post-legalisation psychedelic medicine ecosystem.
This mini-review (2023) provides insights into the complex mechanisms of action of serotonergic psychedelics, such as psilocybin and LSD, emphasizing their activation of serotonin receptors, particularly 5-HT2A receptors, leading to alterations in perception, cognition, and emotions. The review explores the role of neuroplasticity in their therapeutic potential for mental health conditions and discusses interactions with other serotonin receptor subtypes and neurotrophin receptors. Additionally, it highlights the emerging interest in developing non-hallucinogenic derivatives to retain therapeutic benefits while minimizing the risk of adverse reactions and explores the potential of psychedelics in post-translational modification of proteins as part of their mechanism of action.
This observational study (n=233) investigates the impact of four weeks of microdosing (MD) on mindfulness and personality traits in adults with ADHD. Findings indicate increased mindfulness and decreased neuroticism post-MD, with no significant changes in other personality traits. The use of conventional ADHD medication or the presence of comorbidities didn't affect the outcomes, suggesting MD may alter stable traits independently of these factors.
This pre-print neuroimaging study (n=49) compared psilocybin and placebo effects on brain patterns and subjective experiences using ultra-high field 7T MRI. Participants who took psilocybin (12mg/70kg, n=22) displayed increased average functional connectivity and a hyperconnected-hyperarousal brain pattern, correlated with profound changes in consciousness, notably feelings of oceanic boundlessness and visionary restructuralization, as measured by the 5D-ASC Rating Scale. This study links these brain dynamics to the phenomenological experiences during the psychedelic state for the first time.
This pre-print review (2023) scrutinizes the role of psychotherapy in psychedelic-assisted psychotherapy (PAP/PAT) for mental health conditions. It underscores a significant research gap in understanding the psychotherapeutic elements within PAT, despite its assumed importance for safety and efficacy. The paper calls for a transdisciplinary approach in future research to optimize PAT clinical outcomes and inform federal guidelines.
This prospective observational study (n=807) analyzed negative psychological responses to psychedelics, defining it as a clinically meaningful decline in mental health four weeks post-use. They found that 16% of participants experienced negative responses, with a notably higher prevalence (31%) among those with a prior diagnosis of personality disorder. The study implies that individuals with a history of personality disorder might face elevated risks with psychedelic use, emphasizing the need for enhanced psychological support and therapeutic alliance in this population.
This epidemiological study (n=2822, n=613 with lifetime psychedelic use) explored associations between naturalistic psychedelic use and psychiatric risks in a US adult sample. Findings showed lifetime psychedelic use linked with more unusual visual experiences throughout life but no direct connection to recent psychotic symptoms. An interaction between lifetime psychedelic use and family history of psychotic or bipolar disorders revealed higher recent psychotic symptoms in individuals with both factors, and lower symptoms without such family history.
This open-label prospective study (n=25) evaluated esketamine nasal spray (ESK-NS) treatment for treatment-resistant depression (TRD). Over three months, patients reported early and sustained improvements in depression, anhedonia, and suicidality, while clinicians detected improvements that varied at different time points.
This systematic review (2023, s=14) examines the effects of MDMA on the male and female sexual response cycles. Among women, MDMA showed increased sexual desire in 4 out of 6 studies, while in men, it exhibited varied effects on desire, arousal, and erectile function. Both genders experienced delayed orgasm but increased intensity and pleasure upon achieving it. Overall, while MDMA generally increased sexual desire and intensified orgasms, it presented conflicting evidence regarding sexual arousal and potentially impaired erectile and ejaculatory function in men.
This randomized controlled pilot study (n=26) investigated the effect of ketamine on resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC) subregions. Contrary to expectations, ketamine did not increase RSFC between these areas but instead led to a transient decrease in vmPFC-amygdala RSFC in individuals with PTSD. These results challenge prior correlations and suggest a need for further exploration and a more nuanced understanding of the neurobiological basis of dissociative phenomena in PTSD.
This neuroimaging study (n=24 ayahuasca users from Santo Daime & case-matched controls) examined the relationship between cortical gene expression markers and brain morphometric changes following repeated ayahuasca use. It found that repeated ayahuasca usage was associated with spatially distributed cortical structural differentiation in sensorimotor areas and de-differentiation in transmodal areas, correlated with dysregulation of 5-HT2A gene expression and genes encoding target receptors. The study suggests preliminary evidence that molecular mechanisms of psychedelic action may influence large-scale brain organization, potentially accounting for behavioural differences in experienced psychedelic users.
This mixed-method study (n=608) explored prolonged adverse effects following psychedelic use, revealing extended challenges persisting for weeks, months, or even years in some cases. One-third of participants experienced problems for over a year, with a sixth enduring these difficulties for over three years. Factors such as knowledge of dosage, drug type, and lower reported difficulty during the experience influenced the duration and range of these challenges. In contrast, guided settings during drug intake appeared to narrow the spectrum of problems.
This re-analysis study (n=20) investigated the impact of acute LSD (75μg) administration on thalamocortical connectivity in healthy volunteers. The study utilized structural and resting-state fMRI to examine the thalamus at the nucleus-specific level. LSD intake was found to increase functional connectivity between the thalamus's ventral complex, pulvinar, and non-specific nuclei, particularly with sensory cortices such as somatosensory and auditory networks, as well as parts of the associative cortex dense in serotonin type 2A receptors. The study also reported decreased connectivity between the striatum and thalamus.
This placebo-controlled study (n=13) investigated the effects of ketamine (3.5-35mg/70kg) on altered states of consciousness (ASCs) and their neural mechanisms. It examined the impact of different doses of ketamine on emotional task-evoked brain activity and various components of dissociation and ASCs. The study found that ketamine-induced ASCs had differential effects on brain activity, with higher depersonalization relieving negative brain states, while dissociative amnesia exacerbated insula activity. These results may provide insights into how specific dissociative states predict the response to ketamine in individuals with depression.
This philosophical article (2023) discusses the compatibility of mystical-type experiences induced by psychedelic substances with naturalism. The author suggests that while mystical insights may align with naturalism by considering the ultimate nature of reality as observation-independent, accessing the fundamental nature of all reality remains a challenging "hard problem." Psychedelics are proposed to enhance awareness of consciousness and the limitations of our reality models, but it is unclear if they provide access to the fundamental nature of all reality. In conclusion, the author contends that mystical-type conceptions about reality may coexist with naturalism but are generally unverifiable, similar to many metaphysical theses.
This study analyzed data from an RCT (n=31) with treatment-resistant depression (TRD) who received therapeutic doses of intravenous ketamine (35 to 70mg/70kg). The research found that a later onset of depression was positively correlated with a better treatment response to ketamine after three days of administration, suggesting that earlier disease onset may be associated with impaired glutamatergic signal transmission and reduced neuroplasticity, which diminishes the response to ketamine. Other demographic and clinical factors, including age, sex, baseline depression score, and dissociative score, didn't significantly correlate with treatment response.
This longitudinal observational study (n=9,732) aimed to investigate potential associations between self-reported psychedelic use and meditation practice in the US and UK adult populations. The study found that psychedelic use during a 2-month period was associated with increased engagement in mindfulness meditation practice, and the subjective experience of insight during psychedelic use was linked to greater involvement in mindfulness and loving-kindness or compassion meditation. Additionally, the research indicated that baseline engagement in loving-kindness or compassion meditation was associated with reduced severity of challenging experiences during psychedelic use.
This experimental study (n=37) explored the integration of psilocybin-assisted neurofeedback in individuals with psychiatric disorders and executive function deficits. The participants received three microdose sessions followed by three psilocybin-assisted neurofeedback sessions. While there were no immediate improvements in experimental tasks assessing executive functions, significant self-reported improvements in daily life executive functions were observed, including working memory, shifting, monitoring, and inhibition, with high effect sizes.
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