Mechanisms of psilocybin on the treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a condition that can develop after a traumatic event, causing distressing symptoms, including intrusive re-experiencing symptoms, alterations in mood and cognition, and changes in arousal and reactivity. Few treatment options exist for patients who find conventional psychotherapy and pharmacotherapy to be inaccessible, ineffective, or intolerable. We explore psilocybin as a potential treatment option for PTSD by examining the neurobiology of PTSD as well as psilocybin's mechanism of action. Based on both pharmacodynamic and psychoanalytic principles, psilocybin may be an underexplored treatment option for patients with PTSD, though further research is required.

Perceived changes in mental health and social engagement attributed to a single psychedelic experience in autistic adults: results from an online survey.

RATIONALE: Anecdotal reports suggest that psychedelic drugs can improve psychological wellbeing and social engagement in autistic people. However, there are few contemporary studies on this topic. OBJECTIVES: To examine autistic participants' experiences with psychedelic drugs and the extent to which they attributed changes in mental health and social engagement to their most 'impactful' psychedelic experience. We also explored associations between these changes and mechanistically important variables (e.g., aspects of the acute psychedelic experience and changes in 'psychological flexibility'). METHODS: Self-selecting autistic participants (n = 233) with high autism quotient scores completed an online survey relating to their most impactful psychedelic experience. Questionnaires assessed the acute psychedelic experience and perceived psychedelic-induced changes in distress, social engagement and psychological flexibility, among other relevant variables. RESULTS: The majority of participants attributed reductions in psychological distress (82%) and social anxiety (78%) and increases in social engagement (70%) to their most 'impactful' psychedelic experience. A substantial minority (20%) also reported undesirable effects such as increases in anxiety with some describing their psychedelic experience as among the most negatively impactful experiences of their lives. The only substantial predictor of reductions in psychological distress was increased psychological flexibility. CONCLUSION: Autistic people attributed changes in mental health and social engagement to a single highly impactful psychedelic experience. The results and their implications are discussed with caution considering the use of a non-experimental design and biased sampling.

Beyond the numbers: reimagining healing with psychedelics for eating disorders.

Psychedelic medicine is currently being evaluated for numerous mental health indications, and there is significant interest in applying these models of care to eating disorders (EDs) given the limited efficacy of available treatment models, especially for those living with anorexia nervosa. Preliminary findings across a number of studies suggest promise. In this commentary, researchers with experience in psychedelics and EDs present a rationale and considerations for the application of psychedelic medicine, including psychedelic-assisted therapy (PAT) for EDs. These contributions are informed by those with lived experience as well as the authors' experiences in the field. By addressing underlying psychological and transpersonal factors and improving treatment engagement, psychedelic medicine, though not without risks, may offer a valuable adjunct to existing treatments, enhancing overall outcomes for some living with an ED. This commentary also aims to provide a multi-dimensional perspective to inform the field, including with respect to the etiology of these illnesses, as psychedelic medicine becomes more accessible in naturalistic, research and clinical settings.

Psilocybin reduces functional correlation and the encoding of spatial information by neurons in mouse retrosplenial cortex.

Psychedelic drugs have profound effects on perception, cognition and mood. How psychedelics affect neural signaling to produce these effects remains poorly understood. We investigated the effect of the classic psychedelic psilocybin on neural activity patterns and spatial encoding in the retrosplenial cortex of head-fixed mice navigating on a treadmill. The place specificity of neurons to distinct locations along the belt was reduced by psilocybin. Moreover, the stability of place-related activity across trials decreased. Psilocybin also reduced the functional correlation among simultaneously recorded neurons. The 5-HT2AR (serotonin 2A receptor) antagonist ketanserin blocked these effects. These data are consistent with proposals that psychedelics increase the entropy of neural signaling and provide a potential neural mechanism contributing to disorientation frequently reported by humans after taking psychedelics.

History, Hype, and Responsible Psychedelic Medicine: A Qualitative Study of Psychedelic Researchers.

Background Psychedelic medicine is a rapidly growing area of research and policy change. Australia recently became the first country to legalize the prescription of psychedelics and serves as a case study of issues that may emerge in other jurisdictions. Despite their influence as a stakeholder group, there has been little empirical exploration of psychedelic researchers' views on the development of psychedelic research and the ethical concerns. Methods We thematically analysed fourteen interviews with Australian psychedelic researchers. Results Three themes were constructed from the data: 1) coming out of the shadow of the 1960s, 2) challenges and affordances in engaging stakeholders, and 3) growing pains in innovation and translation. Conclusion The results illustrated tensions arising from the rapid growth of psychedelic research from a small group of dedicated individuals with a similar worldview, to a multi-interest, regulated industry. Participants' experiences and viewpoints were influenced by the history of psychedelic research, and this was met with an overarching concern for protecting the field from premature discontinuation, as well as maximizing potential positive impacts. Targets for stakeholder collaboration and initiatives to support responsible innovation in psychedelics include equitable access, sustainable industry involvement, productive research agendas, responsible reporting of evidence, and risk-taking within the relative safety of clinical trials.

Impact of psilocybin on cognitive function: A systematic review.

Psilocybin is a classic psychedelic with demonstrated preliminary clinical efficacy in a range of psychiatric disorders. Evaluating the impact of psilocybin on cognitive function is essential to unravel its potential benefits and risks. In this systematic review, we assessed psilocybin's effect on cognitive function through a comprehensive search of electronic databases from inception to January 2024, identifying 20 articles involving 2,959 participants. While 85% of studies were conducted in healthy volunteers, most of these studies (85%) used macrodoses, ranging from 45 µg/kg to 30 mg/70 kg. Various cognitive aspects were evaluated and yielded mixed results. Global cognitive function, and processing speed remained mostly unchanged in healthy individuals; However, a limited number of studies reported improvements in certain areas such as sustained attention, working memory, and executive function especially in patients with treatment-resistant depression (TRD). Emotional processing was positively modified, particularly in TRD patients. Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive flexibility and creative cognition were noted to initially decline but could potentially improve over time. Additionally, with respect to learning and memory skills, psilocybin showed promise in improving specific memory types such as semantic associations and associative learning, while its effects on episodic and verbal memory have been less pronounced compared to other cognitive enhancers. The observed mixed findings underscore the complexity of psilocybin's cognitive influence. Further research is essential to provide a clearer understanding of psilocybin's impact on cognitive domains and to guide the development of safe and effective interventions.

Probing the functional magnetic resonance imaging response to psilocybin in functional neurological disorder (PsiFUND): study protocol.

Background: Functional neurological disorder (FND) is a common cause of neurological symptoms including paralysis, seizures, and movement disorders. It is often debilitating, is associated with high health and social care costs, and can have a poor prognosis. Functional magnetic resonance imaging (fMRI) has suggested FND is a multi-network disorder; the default mode network (DMN) may be specifically implicated. Converging evidence suggests that other variable mechanisms including dissociation, interoception, and motor agency may be differentially abnormal in people with FND. Psychedelics are currently under investigation for numerous neuropsychiatric disorders and have been shown to disrupt functional networks such as the DMN. Administering psychedelics to people with FND will help us to probe mechanistic theories of the disorder. Protocol: In this open-label neuroimaging study, we will administer 25mg oral psilocybin with psychological support to people with chronic FND (target n = 24). Participants will undergo resting-state and task-based (Libet's clock, a measure of motor agency) fMRI sequences which will be compared in a pre-post manner. Additional mechanistic outcomes including measures of interoception (heartbeat tracking task), somatisation, illness perceptions, imaginative suggestibility, and dissociation will be collected. Data on expectancy, preparedness, and subjective experience of the psychedelic experience will also be gathered. Participants will be followed up for three months following psilocybin administration. fMRI changes in networks such as the DMN will be analysed using seed-based approaches, and additional exploratory analysis of resting-state imaging will take place. Discussion: The study will help us to probe the mechanisms thought to potentially underpin FND. As the first modern study of psychedelics in FND, it will also help us to understand whether psychedelic administration alongside psychological support might be safe and feasible in this patient population.

Classical psychedelics' action on brain monoaminergic systems.

The study of the mechanism of action of classical psychedelics has gained significant interest due to their clinical potential in the treatment of several psychiatric conditions, including major depressive and anxiety disorders. These drugs bind 5-hydroxytryptamine receptors (5-HTR) including 5-HT1AR, 5-HT2AR, 5-HT2BR, and/or 5-HT2CR, as well as other targets. 5-HTRs regulate the activity of ascending monoaminergic neurons, a mechanism primarily involved in the action of classical antidepressant drugs, antipsychotics, and drugs of abuse. Sparse neurochemical data have been produced on the control of monoaminergic neuron activity in response to classical psychedelics. Here we review the available data in order to determine whether classical psychedelics have specific neurochemical effects on serotonergic, dopaminergic, and noradrenergic neurons. The data show that these drugs have disparate effects on each monoaminergic system, demonstrating a complex response with state-dependent and region-specific effects. For instance, several psychedelics inhibit the firing of serotonergic neurons, although this is not necessarily associated with a decrease in serotonin release in all regions. Noradrenergic neuron spontaneous activity also appears to be inhibited by psychedelics, also not necessarily associated with a decrease in noradrenaline release in all regions. Psychedelics influence on dopaminergic systems is also complex as the above-mentioned 5-HTRs may have opposing effects on dopaminergic neuron activity, in a state-dependent manner. There is an apparent lack of clear neuronal signature induced by psychedelics on monoaminergic neuron activity despite specific recurrent mechanisms. This review provides a current summary of the action of psychedelics on monoamine neuromodulators serotonin, dopamine and noradrenaline, compiling reoccurring and contradictory findings demonstrating that a monoamine signature of psychedelics, if applicable, would be state- and region-dependant.

Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI.

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

Classifying Unconscious, Psychedelic, and Neuropsychiatric Brain States with Functional Connectivity, Graph Theory, and Cortical Gradient Analysis.

Accurate and generalizable classification of brain states is essential for understanding their neural underpinnings and improving clinical diagnostics. Traditionally, functional connectivity patterns and graph-theoretic metrics have been utilized. However, cortical gradient features, which reflect global brain organization, offer a complementary approach. We hypothesized that a machine learning model integrating these three feature sets would effectively discriminate between baseline and atypical brain states across a wide spectrum of conditions, even though the underlying neural mechanisms vary. To test this, we extracted features from brain states associated with three meta-conditions including unconsciousness (NREM2 sleep, propofol deep sedation, and propofol general anesthesia), psychedelic states induced by hallucinogens (subanesthetic ketamine, lysergic acid diethylamide, and nitrous oxide), and neuropsychiatric disorders (attention-deficit hyperactivity disorder, bipolar disorder, and schizophrenia). We used support vector machine with nested cross-validation to construct our models. The soft voting ensemble model marked the average balanced accuracy (average of specificity and sensitivity) of 79% (62-98% across all conditions), outperforming individual base models (70-76%). Notably, our models exhibited varying degrees of transferability across different datasets, with performance being dependent on the specific brain states and feature sets used. Feature importance analysis across meta-conditions suggests that the underlying neural mechanisms vary significantly, necessitating tailored approaches for accurate classification of specific brain states. This finding underscores the value of our feature-integrated ensemble models, which leverage the strengths of multiple feature types to achieve robust performance across a broader range of brain states. While our approach offers valuable insights into the neural signatures of different brain states, future work is needed to develop and validate even more generalizable models that can accurately classify brain states across a wider array of conditions.

A Cross-Sectional Survey Investigating Maori and Non-Maori Cancer Patients' Views on Psychedelic-Assisted Therapy in Aotearoa New Zealand.

People with cancer experience higher rates of psychological dysfunction than the general population, with extreme inequity among indigenous people. Psychedelic-assisted therapy (PAT) is a reemerging area with promising evidence as a treatment for mental health difficulties. The current study aimed to investigate the perceptions of PAT in indigenous (Maori) and non-indigenous cancer patients in Aotearoa, New Zealand. Eighty-five cancer patients (Maori n = 32, non-Maori n = 53) completed a brief anonymous survey assessing demographics, psychological factors, and awareness and perceptions of PAT. Participants were recruited online (via social media and cancer support e-mail lists) and in person at Auckland City Hospital. Maori had significantly poorer psychological well-being than non-Maori. All participants had low awareness of this novel treatment and held largely neutral attitudes. Regression analyses revealed that predictors of more favorable attitudes toward PAT included greater awareness of psychedelics, advanced cancer stage, younger age, poorer holistic well-being, greater demoralization, and prioritizing treatment effectiveness over possible risks and uncertainty. The current study provides a foundational step in exploring perceptions toward PAT in indigenous and non-indigenous groups. These results have the potential to shape future research trials investigating PAT and further highlight the importance of indigenous involvement in the psychedelic research space.

Psychedelics as a tool for a more connected and sustainable world? Considering the importance of rituals, boundaries, and commitment.

Despite the surge of interest in psychedelic research in the past decade, largely due to the promise of psychedelics for improving mental health outcomes, there has been comparatively little discussion about the social and environmental consequences of psychedelic drug use. While there is growing evidence to suggest psychedelics could foster a greater connection to the natural world and improve social relationships, such positive repercussions are far from guaranteed. In this commentary, we focus on LSD, psilocybin and especially MDMA, and outline three insights we came to see as crucial to creating beneficial outcomes: 1) the importance of setting and rituals, 2) the establishment of boundaries, and 3) understanding the long-term commitment required. These insights are grounded in the history of psychedelics, which is intimately intertwined with ritualised use, yet the process of commercialisation of these substances threatens to strip away important contextual factors. Creating boundaries around when, how and with whom psychedelics are used have been found to protect recreational users from harm and could also be instrumental in steering commercial interests to align with socio-environmental goals. Finally, far from being a 'quick fix' for social or environmental problems, the use of psychedelics requires sustained engagement to integrate the insights obtained. Whereas we remain optimistic about the transformative potential of psychedelics for social relationships and the environment, we also emphasise the need for a more cautious, considered approach if we are to harness the benefits and minimise the challenges of psychedelic drug use.

Antidepressant and anxiolytic effects of activating 5HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them - A scoping review of available literature.

Psychedelic drugs that activate the 5HT2A receptor have long been the target of extensive clinical research, particularly in models of psychiatric illness. The aim of this literature review was to investigate the therapeutic effects of 5HT2A receptor activation in the anterior cingulate cortex (ACC) and the respective mechanisms that underlie them. Based on the available research, I suggest that 5HT2A receptors in the ACC exert profound changes in excitatory neurotransmission and brain network connectivity in a way that reduces anxious preoccupation and obsessional thoughts, as well as promoting cognitive flexibility and long-lasting mood improvements in anhedonia. This is possibly due to a complex interplay with glutamate and gamma-butyric acid neurotransmission, particularly 5HT2A activation enhances α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signalling, thus altering the ratio of AMPA to N-methyl-D-Aspartate (NMDA) activity in the ACC, which can dismantle previously established neuronal connections and aid the formation of new ones, an effect that may be beneficial for fear extinction and reversal learning. Psychedelics potentially change intra- and internetwork connectivity, strengthening connectivity from the dorsal ACC / Salience Network to the Default Mode Network (DMN) and Central Executive Network (CEN), which correlates with improvements in attentional shifting and anti-anhedonic effects. Additionally, they may decrease inhibitory influence of the DMN over the CEN which may reduce overevaluation of internal states and ameliorate cognitive deficits. Activation of ACC 5HT2A receptors also has important downstream effects on subcortical areas, including reducing amygdala reactivity to threatening stimuli and enhancing mesolimbic dopamine, respectively improving anxiety and the experience of natural rewards.

Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors.

The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several ß-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with ß-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, ß-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.

Refractory CRPS pain treated with psilocybin: A case report.

Psilocybin shows promise as a treatment for CRPS, offering significant pain relief and functional improvement in a patient with refractory symptoms. This case highlights the need for further research into psilocybin's efficacy and optimal dosing for chronic pain management.

A bibliometric analysis of research on psychedelics for depression treatment.

Psychedelics, as a class of potent psychoactive substances, significantly alter sensory perception and mood, thereby profoundly impacting cognition. Increasing evidence indicates that psychedelics can facilitate individual social function and rapidly and sustainably improve symptoms of moderate and severe depression. The growing interest in psychedelics as potential treatments for depression has led to a substantial increase in related publications; however, the overall quantity and quality of these works remain unclear. To address this issue, we conducted a bibliometric analysis of literature on psychedelic drugs for depression published between 2004 and October 2023. Our study meticulously collected 710 publications, allowing for a comprehensive analysis of bibliographic elements such as annual publication trends, authorship, country of origin, institutional affiliations, journals, and keywords. By visualizing trends, emerging frontiers, popular topics, author collaborations, and influential factors in the field of psychedelics for depression, we have enhanced our understanding of advancements in this area. On this basis, we assert that the regulation of psychedelic drugs is necessary, but it should not hinder the scientific research progress.

Low-dose psilocybin in short-lasting unilateral neuralgiform headache attacks: results from an open-label phase Ib ascending dose study.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks (SUNHA) are trigeminal autonomic cephalalgias that feature intense and recurrent paroxysms of pain and autonomic symptoms. Many patients are left with debilitating symptoms despite best-available treatment. Psychedelics, such as the serotonin 2A partial agonist psilocybin, have shown promise in related disorders such as migraine and cluster headache. In this open-label phase Ib ascending dose study, we aimed to assess the effects of low-dose oral psilocybin with psychological support in six to 12 patients with chronic SUNHA. Study objectives were to determine effects on cognition, as well as safety, tolerability, and effects on headache severity and frequency. METHODS: Oral psilocybin in ascending doses of 5, 7.5, and 10 mg (one dose per session; three dosing sessions in total) were administered. Cognition was assessed via the Cambridge Neuropsychological Tests Automated Battery. Headache attacks were assessed via headache diaries and the six-item Headache Impact Test (HIT-6). Subjective dose intensity was assessed via the five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). The study was terminated early due to recruitment difficulties; four patients were enrolled, three of whom were study completers. Post hoc, we undertook a thematic analysis of the applicable free-text clinical trial notes from the dosing and subsequent visits (n = 22). An inductive method was employed to establish emergent themes. RESULTS: No significant adverse events were recorded. We were unable to collect data as planned on cognitive function during the acute experience due to high ratings of subjective dose intensity (mean 5D-ASC scores 37.8-45.7). The impact of the headaches remained severe throughout the duration of the trial (HIT-6 mean scores 64.3-65.7). There were limited effects on headache duration and severity based on the diaries; however, mean daily attack frequency decreased by >50% in two participants at final follow-up (22.9 to 11.0 and 56.4 to 28.0, respectively). Completing participants and their clinicians recorded "much" (two participants) or "minimal" improvements (one participant) at final follow-up via the Clinical Global Impression rating scale. Thematic analysis indicated that psychological insights were key features of participants' experience; these insights included re-configured relationships to their headache pain. CONCLUSION: The study met with recruitment difficulties and cognition could not be assessed during the acute experience due to subjective dose intensity, likely mediated in part by expectancy effects. The clinical results provide no conclusive evidence for the use of psilocybin in SUNHA. We suggest that accounting for psychological factors in chronic SUNHA may be an important facet of treatment.

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.

Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response.

BACKGROUND: Psychedelic-assisted therapy (PAT) is permitted in Switzerland under its limited medical use program. Data from patients in this program represent a unique opportunity to analyze the real-world practice of PAT. AIMS: This study compared the subjective effects of lysergic acid diethylamide (LSD) and psilocybin between patients undergoing PAT and healthy volunteers. For the patients, it also investigated the relationship between antidepressant effects and six measures of acute drug effects. METHODS: We compared data on acute psychedelic drug effects between 28 PAT patients with data from 28 healthy participants who participated in a randomized, double-blind crossover trial. All participants received varying doses of psilocybin and LSD. Subjective effects were assessed on an hourly basis during the acute drug effects, and the Mystical Experience Questionnaire (MEQ) was completed retrospectively. For patients, depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ratings of overall drug effect and mystical experience were similar across groups. Compared with healthy controls, patients reported lower ratings of ego dissolution. Patients showed a significant decrease in MADRS scores, and the greatest predictor of antidepressant outcome was relaxation during the PAT session. We did not observe a relationship between mystical-type experiences and antidepressant effects. Most patients experienced mild adverse effects which resolved within 48 h. CONCLUSION: PAT reduced depressive symptoms in this heterogeneous patient group. Patients may experience more challenging psychedelic effects and reduced ego dissolution. Hourly assessment of drug effects may predict clinical outcomes better than retrospectively assessed mystical experiences, and the impact of relaxation during PAT should be investigated further.

Going Underground: Demographics, Services, and Best Practices Endorsed by Practitioners Providing Support for Naturalistic Psychedelic Use.

Psychedelic-assisted therapy (PAT) has shown preliminary efficacy for psychiatric and physical health conditions. Although some people report naturalistic psychedelic use with so-called "underground" practitioners, little is known about PAT that occurs outside of controlled clinical settings or perspectives of these practitioners. We conducted an anonymous online survey of individuals who reported providing psychedelic support services (e.g. trip sitting and/or preparatory/follow-up psychotherapy) in naturalistic settings. We investigated demographics, including education and licensing, details about services provided, and reported client outcomes. Among 107 participants, 40.2% held a full or in-progress license and 44.9% had not obtained a relevant graduate degree. Almost all participants reported pre-screening clients before treatment, offering preparation, integration, and trip-sitting services, and most employed a range of therapeutic modalities, centering primarily on non-directive approaches. Participants reported that clients most commonly consumed psilocybin, and treated numerous conditions, primarily aligning with indications targeted in psychedelic clinical research. Perceptions of clients' symptom changes were largely positive, although a small proportion reported worsened personality disorder symptoms. Further research delineating client and practitioner perspectives of naturalistic PAT services is warranted, and such work may shed light on the benefits and risks specific to naturalistic PAT as well as inform best practices for practitioners.