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.

Measuring psychotherapeutic processes in the context of psychedelic experiences: Validation of the General Change Mechanisms Questionnaire (GCMQ).

BACKGROUND: Therapeutic and salutogenic effects of psychedelic drugs have been attributed to psychotherapeutic or psychotherapy-like processes that can unfold during the acute psychedelic experience and beyond. Currently, there are no psychometric instruments available to comprehensively assess psychotherapeutic processes (as conceptualized by empirical psychotherapy research) in the context of psychedelic experiences. AIMS: We report the initial validation of the General Change Mechanisms Questionnaire (GCMQ), a self-report instrument designed to measure five empirically established general change mechanisms (GCMs) of psychotherapy-(1) resource activation, (2) therapeutic relationship, (3) problem actuation, (4) clarification, and (5) mastery-in the context of psychedelic experiences. METHODS: An online survey in a sample of 1153 English-speaking and 714 German-speaking psychedelic users was conducted to evaluate simultaneously developed English- and German-language versions of the GCMQ. RESULTS: The theory-based factor structure was confirmed. The five GCMQ scales showed good internal consistency. Evidence for convergent validity with external measures was obtained. Significant associations with different settings and with therapeutic, hedonic, and escapist use motives confirmed the hypothesized context dependence of GCM-related psychedelic experiences. Indicating potential therapeutic effects, the association between cumulative stressful life events and well-being was significantly moderated by resource activation, clarification, and mastery. Factor mixture modeling revealed five distinct profiles of GCM-related psychedelic experiences. CONCLUSION: Initial testing indicates that the GCMQ is a valid and reliable instrument that can be used in future clinical and nonclinical psychedelic research. The five identified profiles of GCM-related experiences may be relevant to clinical uses of psychedelics and psychedelic harm reduction.

5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.

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.

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.

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.

A thematic analysis of MDMA-related harm and harm reduction experiences and knowledge in Aotearoa New Zealand.

BACKGROUND: Methylenedioxymethamphetamine (MDMA) is a popular drug worldwide and use is prevalent in Aotearoa New Zealand. Although associated with some significant harms, including fatalities, MDMA is ultimately less harmful than other commonly consumed drugs. We aimed to expand the understanding of MDMA harm and harm reduction strategies from a consumer perspective so that national harm reduction efforts can be better informed. METHODS: We conducted 14 semi-structured focus group discussions including 60 people (aged 18-67, median = 21) who use MDMA in the Southern region of Aotearoa New Zealand to explore their thoughts and experiences regarding MDMA associated harm and harm reduction. Reflexive thematic analysis was conducted from a critical realist perspective. RESULTS: Five themes were generated; (1) Mindset and setting matters; (2) Looking after your body and mind, not overdoing it; (3) Other substances increase risk and harm; (4) Trusted friends and peers are protective; and (5) Valid information is key for healthy self-determination; and one subtheme 5.1) Drug checking is essential harm reduction. CONCLUSIONS: We discuss the implications for MDMA consumers and aim to inform national drug policy and the harm reduction practices of consumers and organisations, for the ultimate purpose of reducing MDMA-related harm in Aotearoa New Zealand.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

Metabolism and cytotoxicity studies of the two hallucinogens 1cP-LSD and 4-AcO-DET in human liver and zebrafish larvae models using LC-HRMS/MS and a high-content screening assay.

The continuous emergence of new psychoactive substances (NPS) attracted a great deal of attention within recent years. Lately, the two hallucinogenic NPS 1cP-LSD and 4-AcO-DET have appeared on the global market. Knowledge about their metabolism to identify potential metabolic targets for analysis and their cytotoxic properties is lacking. The aim of this work was thus to study their in vitro and in vivo metabolism in pooled human liver S9 fraction (pHLS9) and in zebrafish larvae (ZL) by means of liquid chromatography-high-resolution tandem mass spectrometry. Monooxygenases involved in the initial metabolic steps were elucidated using recombinant human isozymes. Investigations on their cytotoxicity were performed on the human hepatoma cell line HepG2 using a multiparametric, fluorescence-based high-content screening assay. This included measurement of CYP-enzyme mediated effects by means of the unspecific CYP inhibitor 1-aminbenzotriazole (ABT). Several phase I metabolites of both compounds and two phase II metabolites of 4-AcO-DET were produced in vitro and in vivo. After microinjection of 1cP-LSD into the caudal vein of ZL, three out of seven metabolites formed in pHLS9 were also detected in ZL. Twelve 4-AcO-DET metabolites were identified in ZL after exposure via immersion bath and five of them were found in pHLS9 incubations. Notably, unique metabolites of 4-AcO-DET were only produced by ZL, whereas 1cP-LSD specific metabolites were found both in ZL and in pHLS9. No toxic effects were observed for 1cP-LSD and 4-AcO-DET in HepG2 cells, however, two parameters were altered in incubations containing 4-AcO-DET together with ABT compared with incubations without ABT but in concentrations far above expected in vivo concentration. Further investigations should be done with other hepatic cell lines expressing higher levels of CYP enzymes.

[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.

Medical Uses and Adverse Effects of Psilocybin.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds repors that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(3):23f03652. Author affiliations are listed at the end of this article.

What is needed for the roll-out of psychedelic treatments?

PURPOSE OF REVIEW: The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention? RECENT FINDINGS: Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing. SUMMARY: Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.

The psychedelic call: analysis of Australian Poisons Information Centre calls associated with classic psychedelics.

INTRODUCTION: The global use of certain classical psychedelics has increased in recent years, but little is known about their spectrum of toxicity within Australia. We aim to describe calls to New South Wales Poisons Information Centre relating to exposures to classical psychedelics including lysergic acid diethylamide, psilocybin, N,N-dimethyltryptamine, ayahuasca, mescaline and ibogaine. METHODS: This is a retrospective observational study of calls to New South Wales Poisons Information Centre between January 2014 and December 2022. We identified exposures to classical psychedelics within New South Wales Poisons Information Centre database and measured the annual number of exposures, source of call (hospital, health care worker, member of the public), co-ingested substances, clinical features and advice given. RESULTS: There were 737 calls related to relevant psychedelic exposures; 352 (47.8 per cent) to lysergic acid diethylamide, 347 (47.0 per cent) to psilocybin, 28 (3.8 per cent) to N,N-dimethyltryptamine, 4 (0.5 per cent) to ayahuasca, 4 (0.5 per cent) to mescaline and 2 (0.3 per cent) to ibogaine. Cases were predominantly male (77.2 per cent) and aged between 20 and 74 years (65.6 per cent). Psychedelic calls more than doubled from 45 in 2014 to 105 in 2022 and 625 (85 per cent) of all calls were either from or referred to hospital. Co-ingestion of psychedelics with another substance occurred in 249 (33.8 per cent) of calls and the most frequent clinical features related to single substance psychedelic exposures were hallucinations (27.6 per cent), gastrointestinal symptoms (21.7 per cent) and tachycardia (18.1 per cent). Seizures occurred in 2.9 per cent of single substance psychedelic exposures. DISCUSSION: Increasing incidence of psychedelic exposure calls, including those reporting significant toxicity, likely reflects increasing community use. This may in part be driven by increasing interest in psychedelic assisted psychotherapy trials subsequently increasing public awareness. CONCLUSION: Relatively high poisoning severity contrasts with safety within clinical trials of psychedelic assisted psychotherapy that may relate to the uncontrolled nature of community use which is mitigated within clinical trial environments. Education about safe use may be useful.