[MDMA-assisted therapy for PTSD].

MDMA is a potential novel treatment for post-traumatic stress disorder (PTSD). Our goal is to review current knowledge on MDMA and its use in MDMA-assisted psychotherapy for PTSD. Literature searches were done on PubMed, Web of Science and Google Scholar and references reviewed in identified articles. MDMA-assisted therapy for PTSD usually consists of a few preparatory sessions before two or three sessions where one or two oral doses of MDMA are given along with supportive psychotherapy. The therapy is delivered in the presence of two therapists for about eight hours each time. In addition, the patient receives up to 9 integrative sessions in due course. This use of MDMA as a part of psychotherapy for PTSD is proposed to lessen the psychological distress that often arises in the processing of traumatic events to facilitate the treatment process and reduce the risk of drop-out. Recent studies indicate that MDMA-assisted psychotherapy reduces PTSD symptoms and is generally well tolerated. These studies are necessary if this MDMA-assisted treatment is to be approved by licensing authorities. There is an urgent need for new effective treatments for PTSD and for comparisons between this MDMA-assisted psychotherapy and currently approved psychotherapies with and without MDMA-use.

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk.

BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.

Psychedelics and Evidence-based Psychotherapy: A Systematic Review with Recommendations for Advancing Psychedelic Therapy Research.

Administration of psychedelics for mental health treatment, typically referred to as "psychedelic-assisted therapy," is a broad term with a very heterogeneous implementation. Despite increasing interest in the clinical application of psychedelic compounds for psychiatric disorders, there is no consensus on how to best integrate the psychedelic experience with evidence-based psychotherapeutic treatment. This systematic review provides a timely appraisal of existing approaches to combining psychotherapy with psychedelics and provides clear recommendations to best develop, optimize, and integrate evidence-based psychotherapy with psychedelic administration for straightforward scientific inference and maximal therapeutic benefit.

Personality traits explain the relationship between psychedelic use and less depression in a comparative study.

Interest in psychedelics is increasing due to the potential for improved mental health and quality of life. However, adverse effects on mental health are still a concern. Personality traits have been suggested to both influence the psychedelic experience and mental health, and even be changed by psychedelic use. The present study describes for the first time a national sample of Swedish psychedelic users (n = 400) compared to a sex and age-matched control-group of non-users (n = 400) regarding mental health variables (depression, insomnia, problematic alcohol and drug use, and dissociation) and personality (Big Five). Data was collected in an online survey including individuals from 16 years of age who had at least one psychedelic experience. The main results reported psychedelic users as less depressed (Patient Health Questionnaire-9; PHQ-9) (d = - 0.29) and having more use of drugs (Drug Use Disorders Identification Test; DUDIT) (d = 1.27). In the Big Five personality traits, openness differed notably (d = 1.72), and the between-group effects in PHQ-9 were explained by lower neuroticism. Our findings reveal that psychedelic users report less depression and higher drug use, and this is partly due to personality traits. These results have implications on how we view psychedelic users and the use of psychedelic drugs.

Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis.

OBJECTIVE: To determine the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Five electronic databases of published literature (Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index and Conference Proceedings Citation Index, and PsycInfo) and four databases of unpublished and international literature (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA), and handsearching of reference lists, conference proceedings, and abstracts. DATA SYNTHESIS AND STUDY QUALITY: Information on potential treatment effect moderators was extracted, including depression type (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). Data were synthesised using a random effects meta-analysis model, and observed heterogeneity and the effect of covariates were investigated with subgroup analyses and metaregression. Hedges' g was used as a measure of treatment effect size, to account for small sample effects and substantial differences between the included studies' sample sizes. Study quality was appraised using Cochrane's Risk of Bias 2 tool, and the quality of the aggregated evidence was evaluated using GRADE guidelines. ELIGIBILITY CRITERIA: Randomised trials in which psilocybin was administered as a standalone treatment for adults with clinically significant symptoms of depression and change in symptoms was measured using a validated clinician rated or self-report scale. Studies with directive psychotherapy were included if the psychotherapeutic component was present in both experimental and control conditions. Participants with depression regardless of comorbidities (eg, cancer) were eligible. RESULTS: Meta-analysis on 436 participants (228 female participants), average age 36-60 years, from seven of the nine included studies showed a significant benefit of psilocybin (Hedges' g=1.64, 95% confidence interval (CI) 0.55 to 2.73, P<0.001) on change in depression scores compared with comparator treatment. Subgroup analyses and metaregressions indicated that having secondary depression (Hedges' g=3.25, 95% CI 0.97 to 5.53), being assessed with self-report depression scales such as the Beck depression inventory (3.25, 0.97 to 5.53), and older age and previous use of psychedelics (metaregression coefficient 0.16, 95% CI 0.08 to 0.24 and 4.2, 1.5 to 6.9, respectively) were correlated with greater improvements in symptoms. All studies had a low risk of bias, but the change from baseline metric was associated with high heterogeneity and a statistically significant risk of small study bias, resulting in a low certainty of evidence rating. CONCLUSION: Treatment effects of psilocybin were significantly larger among patients with secondary depression, when self-report scales were used to measure symptoms of depression, and when participants had previously used psychedelics. Further research is thus required to delineate the influence of expectancy effects, moderating factors, and treatment delivery on the efficacy of psilocybin as an antidepressant. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023388065.

Mechanisms of therapeutic change after psychedelic treatment in OCD.

Novel treatments are required for the 30-50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.

Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases.

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as "Psychoactive" in Adult Zebrafish Screens.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF3 substitutions in the ortho position of the phenyl ring of the N-benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

Possible Role of Cannabis in the Management of Neuroinflammation in Patients with Post-COVID Condition.

The post-COVID condition (PCC) is a pathology stemming from COVID-19, and studying its pathophysiology, diagnosis, and treatment is crucial. Neuroinflammation causes the most common manifestations of this disease including headaches, fatigue, insomnia, depression, anxiety, among others. Currently, there are no specific management proposals; however, given that the inflammatory component involves cytokines and free radicals, these conditions must be treated to reduce the current symptoms and provide neuroprotection to reduce the risk of a long-term neurodegenerative disease. It has been shown that cannabis has compounds with immunomodulatory and antioxidant functions in other pathologies. Therefore, exploring this approach could provide a viable therapeutic option for PCC, which is the purpose of this review. This review involved an exhaustive search in specialized databases including PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, and Clinical Trials. Phytocannabinoids, including cannabidiol (CBD), cannabigerol (CBG), and Delta-9-tetrahydrocannabinol (THC), exhibit significant antioxidative and anti-inflammatory properties and have been shown to be an effective treatment for neuroinflammatory conditions. These compounds could be promising adjuvants for PCC alone or in combination with other antioxidants or therapies. PCC presents significant challenges to neurological health, and neuroinflammation and oxidative stress play central roles in its pathogenesis. Antioxidant therapy and cannabinoid-based approaches represent promising areas of research and treatment for mitigating adverse effects, but further studies are needed.

Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial.

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.

"Everything is kind of the same except my mind is with me": exploring cannabis substitution in a sample of adults in early recovery from an opioid or stimulant addiction.

BACKGROUND: Recovery from addiction is frequently equated with abstinence. However, some individuals who resolve an addiction continue to use substances, including via substitution (i.e., increased use of one substance after eliminating/ reducing another). Substitution may play a distinct role during early recovery (≤ 1 year), as this period is marked by dramatic change and adjustment. Cannabis is one of the most used substances and is legal for medical and recreational use in an increasing number of states. Consequently, cannabis an increasingly accessible substitute for substances, like fentanyl, heroin, cocaine and methamphetamine, with higher risk profiles (e.g., associated with risk for withdrawal, overdose, and incarceration). METHODS: Fourteen participants reported that they had resolved a primary opioid or stimulant addiction and subsequently increased their cannabis use within the previous 12 months. Using grounded theory, the interviewer explored their experiences of cannabis use during early recovery. Data were analyzed in three stages: line by line coding for all text related to cannabis use and recovery, focused coding, and axial coding to generate a theory about recovery with cannabis substitution. The motivational model of substance use provided sensitizing concepts. RESULTS & DISCUSSION: The final sample included eight men and six women ranging in age from 20 to 50 years old. Three participants resolved an addiction to methamphetamine and the remaining 11, an addiction to opioids. Participants explained that cannabis was appealing because of its less harmful profile (e.g., no overdose risk, safe supply, few side effects). Participants' primary motives for cannabis use included mitigation of psychiatric symptoms, withdrawal/ cravings, and boredom. While cannabis was effective toward these ends, participants also reported some negative side effects (e.g., decreased productivity, social anxiety). All participants described typical benefits of recovery (e.g., improved self-concept, better relationships) while continuing to use cannabis. Their experiences with and beliefs about substitution suggest it can be an effective strategy for some individuals during early recovery. CONCLUSIONS: Cannabis use may benefit some adults who are reducing their opioid or stimulant use, especially during early recovery. The addiction field's focus on abstinence has limited our knowledge about non-abstinent recovery. Longitudinal studies are needed to understand the nature of substitution and its impact on recovery over time.

Associations of U.S. state-level COVID-19 policies intensity with cannabis sharing behaviors in 2020.

BACKGROUND: Cannabis use before the COVID-19 pandemic for many involved sharing prepared cannabis for inhalation, practices that were less prevalent during the pandemic. State-level COVID-19 containment policies may have influenced this decrease. This study examined the extent to which the intensity of state-level COVID-19 policies were associated with individual-level cannabis sharing. Findings have the potential to guide harm reduction policies for future respiratory pandemics and seasonal respiratory virus waves. METHODS: This study used cross-sectional individual-level data from the COVID-19 Cannabis Study, an anonymous U.S.-based web survey on cannabis use disseminated during the early phase of the pandemic (Full sample N = 1,883). We combined individual-level data with state-level policy data from Kaiser Family Foundation's State COVID-19 Data and Policy Actions for three time-points from June to August 2020 that overlapped with the survey period. Cannabis sharing was dichotomized as any versus no sharing. We adapted a previously published coding framework to score the intensity of COVID-19 policies implemented in each U.S. state and averaged the policy score across the time period. We then used Poisson regression models to quantify the associations of the average state-level COVID-19 policy score with cannabis sharing during the pandemic. RESULTS: Participants (n = 925) reporting using inhalation as a mode for cannabis use were included in this analysis. Most respondents were male (64.1%), non-Hispanic White (54.3%), with a mean age of 33.7 years (SD 8.8). A large proportion (74.9%) reported sharing cannabis during the pandemic. Those who shared cannabis more commonly lived in states with a lower average policy score (16.7, IQR 12.3-21.5) compared to those who did not share (18.6, IQR 15.3-25.3). In adjusted models, the prevalence ratio of any cannabis sharing per every 5-unit increase in the average COVID-19 policy score was 0.97 (95% CI 0.93, 1.01). CONCLUSIONS: Fewer individuals shared cannabis in states with more intense COVID-19 containment policies compared to those in states with less intense policies. Individuals who use cannabis may be willing to make changes to their behavior and may further benefit from specific and directed public health messaging to avoid sharing during respiratory infection outbreaks.

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. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3-38.3 min) compared to placebo-with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ; ACTRN12621000436875.

Bio-Psycho-Spiritual Perspectives on Psychedelics: Clinical and Ethical Implications.

Psychedelics have again become a subject of widespread interest, owing to the reinvigoration of research into their traditional uses, possible medical applications, and social implications. As evidence for psychedelics' clinical potential mounts, the field has increasingly focused on searching for mechanisms to explain the effects of psychedelics and therapeutic efficacy of psychedelic-assisted therapy (PAT). This paper reviews three general frameworks that encompass several prominent models for understanding psychedelics' effects-specifically, neurobiological, psychological, and spiritual frameworks. Following our review, the implications of each framework for ethics and professional competencies in the implementation of psychedelics as medicines are explored. We suggest that interdisciplinary education may be necessary to improve communication between researchers, develop models that effectively incorporate multiple levels of analysis, and facilitate collaboration between professionals with diverse backgrounds in the implementation of psychedelic medicines. We also address pitfalls associated with overemphasis on neuro-mechanisms, risks associated with instigating vulnerable states of consciousness, and hurdles associated with the integration of spiritual frameworks in medicine. Ultimately, as psychedelics push the boundaries of explanatory frameworks focused on one level of analysis, developing new and more useful models to reflect knowledge being produced in this field should be a central aim of psychedelic science going forward.

Are Psychedelic Experiences Transformative? Can We Consent to Them?

Psychedelic substances have great promise for the treatment of many conditions, and they are the subject of intensive research. As with other medical treatments, both research and clinical use of psychedelics depend on our ability to ensure informed consent by patients and research participants. However, some have argued that informed consent for psychedelic use may be impossible, because psychedelic experiences can be transformative in the sense articulated by L. A. Paul (2014). For Paul, transformative experiences involve either the acquisition of knowledge that cannot be obtained in any other way or changes in the self. Either of these characteristics may appear to undermine informed consent. This article argues, however, that there is limited evidence that psychedelic experiences are transformative in Paul's sense, and that they may not differ in their transformative features from other common medical experiences for which informed consent is clearly possible. Further, even if psychedelic experiences can be transformative, informed consent is still possible. Because psychedelic experiences are importantly different in several respects from other medical experiences, this article closes with recommendations for how these differences should be reflected in informed consent processes.