Emerging evidence suggests that mystical experiences mediate the therapeutic effects of psychedelic-assisted therapy. The current study examines associations between mystical experiences and components of “set” (positive mindset, participant intentions, and spirituality) and “setting” (perceived positivity of the dosing environment) in the context of psilocybin-assisted therapy for alcohol use disorder (AUD). Twenty adults with moderate-to-severe AUD participated in a 10-week psilocybin-assisted therapy protocol including two open-label 25 mg psilocybin sessions (Session 1 at week 3; Session 2 at week 7) and weekly counseling. Mystical experiences were assessed via the Mystical Experience Questionnaire (MEQ). Precursor variables—participant spirituality, spiritual intentions, clarity of intentions, mindset, and perceptions of the treatment setting—were measured using validated self-report scales. Spearman correlations were used to evaluate associations between precursor variables and MEQ scores and between spirituality and spiritual intentions. Changes across sessions were examined using Wilcoxon signed-rank tests. Intensity of mystical experiences was significantly associated with spirituality (Session 1: r s = 0.76, p < 0.0001), spiritual intentions (Session 1: r s = 0.71, p < 0.001; Session 2: r s = 0.66, p < 0.001), positive mindset (Session 2: r s = 0.52, p = 0.024), and positive perceptions of setting (Session 2: r s = 0.46, p = 0.046). Spirituality was significantly correlated with spiritual intentions at both sessions (Session 1: r s = 0.77, p < 0.0001; Session 2: r s = 0.63, p < 0.005). Mystical experience intensity significantly increased from Session 1 to Session 2 (Wilcoxon S = 48.5, p = 0.033), while no significant changes were observed in precursor variables across sessions (Wilcoxon S = [−8, 33], p = [0.192, 0.953]). Change in MEQ scores was not significantly associated with changes in any of the precursor variables across sessions (r s = [−0.28, 0.18], p = [0.268, 0.804]). Findings suggest that multiple aspects of set and setting—particularly, spiritual intentions, spirituality, mindset, and perceptions of the treatment setting—may be important predictors of mystical experience intensity during psychedelic-assisted therapy. While spirituality was more strongly associated with mystical experiences during the initial dosing session, mindset and setting became more strongly associated in the subsequent session. Future research should evaluate strategies for optimizing environmental and psychological factors—including structured intention-setting exercises—to enhance therapeutic outcomes.

Background:Psychedelic-assisted psychotherapy has shown promising results for treating alcohol use disorder (AUD) and other mental health conditions. Although the precise mechanisms of psychedelic therapies remain unclear, many studies report increased feelings of connectedness following psychedelic experiences. Specifically, both nature relatedness (one's subjective sense of being connected to nature) and social connectedness (feelings of comprehensive social closeness) have been shown to increase with psychedelic use, and greater connectedness in these domains has been associated with enhanced health and well-being. The current study examined whether a nature-themed video intervention presented to participants undergoing psilocybin-assisted psychotherapy would differentially affect nature relatedness compared with social connectedness in adults with AUD. Methods:A total of 20 participants were randomized to either the visual healing condition (viewing a 42-min nature video; N = 10) or the standard setting condition (guided body scan; music with eyeshades; N = 10). Nature relatedness and social connectedness were measured using the Nature Relatedness Scale (NRS-6) and the Social Connectedness Scale-Revised (SCS-R) at baseline and 2 weeks after the psilocybin session. Results:A significant between-group difference was observed in change in nature relatedness pre-to-postpsilocybin session [χ2(1) = 5.74, p = 0.02]. Nature relatedness significantly increased in the visual healing group [median change in NR-6 = 0.33, range = (-0.17, 0.67), p = 0.01], but not in the standard setting group [median change = 0.00; range = (-0.17, 0.33), p = 0.50]. No significant between-group differences were observed for change in social connectedness [χ2(1) = 0.89, p = 0.35], and no significant overall change in social connectedness was observed across groups [median change = -1.00, range = (-27, 20), p = 0.90]. Conclusions:Viewing a nature-themed video may enhance nature relatedness among individuals undergoing psilocybin-assisted psychotherapy for AUD. Future research should investigate the effects of real-life nature immersion and explore nature relatedness and other forms of connectedness as potential therapeutic targets in psychedelic-assisted and other psychotherapies NCT04410913.

Introduction: As opioid-related drug overdoses remain a public health crisis, there is a critical need for innovative approaches to developing safer analgesics with improved safety profiles. BDH-001 is a fixed-dose combination of low-dose buprenorphine (BUP) and cannabidiol (CBD) being developed as a safer analgesic than currently available opioids. The purpose of this study was to examine the analgesic and opioid-sparing effects of BDH-001 and to complete an in vivo safety assessment in rats. Methods: Analgesic effect of BDH-001 was assessed using the chronic constriction injury model of chronic neuropathic pain with pain threshold assessed via Von Frey testing. Drug-drug interaction effects on pharmacokinetic (PK) parameters were assessed in a single dose PK study in rodents. The effects on respiratory depression were also assessed and confirmed in two separate rodent studies performing blood gas analysis and measuring O2 saturation. Results: BDH-001 (combination of subanalgesic BUP dose and CBD) resulted in statistically significant increases in pain threshold compared to saline (p < 0.001), CBD alone (p < 0.01), and BUP alone (p < 0.05). The half-life of BUP was significantly shorter in the presence of CBD compared to BUP alone (p = 0.008), with no significant changes in any other BUP pharmacokinetic parameter assessed. CBD was found to attenuate BUP-induced respiratory depression in rats when assessing blood gases (p < 0.05) and O2 saturation (p < 0.05) over several time bins. Conclusions: Data obtained in the present study indicate the addition of CBD to BUP was opioid-sparing and attenuated BUP- but not morphine-induced respiratory depression. There was no evidence these findings were the result of a PK interaction. Results support the hypothesis that BDH-001, a fixed-dose combination of BUP and CBD, may provide effective analgesia with a more favorable safety profile.

Introduction: Serotonergic psychedelics, serotonin 2A receptor agonists such as psilocybin that can result in substantially altered states of consciousness, are used in recreational and research settings. The safety of psychedelic experiences in research settings is supported by controlled physical environments, presence of clinical and medical staff to address emergent issues, screening for personal and family history of potential contraindications, and psychoeducational preparation with psychological support. Research settings typically provide psychoeducation to participants verbally and in writing (e.g., informed consent), and such documents and conversations can provide safety-related information-but may also introduce a wide range of expectancies. Such expectancies might involve the specific character of the acute subjective effects of psychedelics, possible side effects, and anticipated outcomes.Methods: To better understand the content of this psychoeducation, we gathered study materials from many psilocybin studies conducted in the past two decades in healthy and therapeutic populations. We conducted a reflexive thematic analysis to better understand these documents.Results: While these documents varied substantially between studies, we identified themes intended to lower levels of risk and optimize therapeutic effects from psychedelic treatments. The most frequently coded themes related to (1) biological and physical safety, (2) psychological safety and well-being, (3) aspects of setting, and (4) potential for expectancies. Prioritizing biological and psychological safety was evident in the materials from all sites. Furthermore, we identify potential contributors to expectancy unrelated to safety and suggest that these extrapharmacological elements be studied systematically in future research.Conclusions: Ideally, future research should strive to maximize safety while attempting to minimize extraneous expectancies.

Importance:Psilocybin shows promise as a treatment for major depressive disorder (MDD).Objective:To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD.Design, Setting, and Participants:In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.Interventions:Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support.Main Outcomes and Measures:The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment.Results:A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.Conclusions and Relevance:Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD.Trial Registration:ClinicalTrials.gov Identifier: NCT03866174.

After a decades-long pause, psychedelics are again being intensely investigated for treating a wide range of neuropsychiatric ailments including depression, anxiety, addiction, post-traumatic stress disorder, anorexia, and chronic pain syndromes. The classic serotonergic psychedelics psilocybin and lysergic acid diethylamide and nonclassic psychedelics 3,4-methylenedioxymethamphetamine and ketamine are increasingly appreciated as neuroplastogens given their potential to fundamentally alter mood and behavior well beyond the time window of measurable exposure. Imaging studies with psychedelics are also helping advance our understanding of neural networks and connectomics. This resurgence in psychedelic science and psychedelic-assisted therapy has potential significance for the fields of neurosurgery and neuro-oncology and their diverse and challenging patients, many of whom continue to have mental health issues and poor quality of life despite receiving state-of-the-art care. In this study, we review recent and ongoing clinical trials, the set and setting model of psychedelic-assisted therapy, potential risks and adverse events, proposed mechanisms of action, and provide a perspective on how the safe and evidence-based use of psychedelics could potentially benefit many patients, including those with brain tumors, pain syndromes, ruminative disorders, stroke, SAH, TBI, and movement disorders. By leveraging psychedelics' neuroplastic potential to rehabilitate the mind and brain, novel treatments may be possible for many of these patient populations, in some instances working synergistically with current treatments and in some using subpsychedelic doses that do not require mind-altering effects for efficacy. This review aims to encourage broader multidisciplinary collaboration across the neurosciences to explore and help realize the transdiagnostic healing potential of psychedelics.

Introduction Psychedelic-assisted therapy with psilocybin has shown promise in Phase 2 trials for alcohol use disorder (AUD). Set and setting, particularly factors facilitating a connection with nature, may positively influence the psychedelic experience and therapeutic outcomes. But to date, randomized controlled trials of interventions to enhance set and setting for psychedelic-assisted therapy are lacking. Methods This was a pilot randomized, controlled trial of Visual Healing, a nature-themed video intervention to optimize set and setting, versus Standard set and setting procedures with two open-label psilocybin 25 mg dosing sessions among 20 participants with AUD. For the first session, participants randomized to Visual Healing viewed nature-themed videos during the preparation session and the “ascent” and “descent” phases of the psilocybin dosing session while participants randomized to the Standard condition completed a meditation during the preparatory session and wore eyeshades and listened to a music playlist throughout the dosing session. For the second session 4 weeks later, participants chose either Visual Healing or Standard procedures. Primary outcomes were feasibility, safety, and tolerability of Visual Healing. Secondary and exploratory outcomes were changes in alcohol use, psychedelic effects, anxiety and stress. Results Nineteen of 20 (95%) randomized participants (mean age 49 ± 11 years, 60% female) completed the 14-week study. During the first psilocybin session, participants viewed an average of 37.9 min of the 42-min video and there were no video-related adverse events. Peak increase in post-psilocybin blood pressure was significantly less for participants randomly assigned to Visual Healing compared to Standard procedures. Alcohol use decreased significantly in both Visual Healing and Standard groups and psychedelic effects, stress, and anxiety were similar between groups. Discussion In this open-label pilot study, viewing Visual Healing videos during preparation and psilocybin dosing sessions was feasible, safe, and well-tolerated among participants with AUD. Preliminary findings suggest that Visual Healing has potential to reduce the cardiovascular risks of psychedelic therapy, without interfering with the psychedelic experience or alcohol-related treatment outcomes. Studies to replicate our findings as well as studies of different set and setting interventions with other psychedelic medications and indications are warranted.

This guide prepares mental health practitioners to (1) identify clients with co-occurring opioid use and mental health disorders in mental health settings and (2) treat these clients with an appropriate opioid use disorder medication. It provides a practical strategy for treating clients in mental health settings with buprenorphine/naloxone or naltrexone extended-release injectable suspension.

INTRODUCTION AND AIMS:Past research investigating syndemic factors and HIV-related outcomes has overlooked the impact of structural conditions on behaviours linked with HIV transmission and disease progression. Given prevalent substance use among our sample, we explored whether four structural conditions indicative of social marginalisation and previously correlated with increased risk for HIV infection demonstrated syndemic (additive/synergistic) effects on: (i) HIV viral suppression; and (ii) self-reported involvement in sexual HIV transmission behaviours among a prospective cohort mostly comprising men of colour who have sex with men (MCSM; i.e. Latino/Hispanic and African American/black men) in Los Angeles County.DESIGN AND METHODS:Data were collected between August 2014 and March 2017. The structural conditions of interest were: current unemployment, recent (≤6 months) incarceration history, 'unstable' accommodation (past month) and remote (>6 months) contact with health-care providers. Generalised estimating equations assessed possible additive effects of experiencing multiple structural conditions, and possible synergistic effects on the HIV-related outcomes.RESULTS:Of 428 participants, nearly half (49%) were HIV-positive at baseline. Involvement in sexual HIV transmission risk behaviours varied over follow-up (22-30%). Reporting ≥2 structural syndemic conditions was significantly associated with reporting sexual HIV transmission risk behaviours among HIV-negative participants, and detectable viral load among HIV-positive participants. Frequent methamphetamine use was consistently associated with the HIV-related outcomes across the final multivariate models.DISCUSSION AND CONCLUSIONS:When developing initiatives to address HIV transmission among marginalised sub-populations including MCSM, we must holistically consider systemic and structural issues (e.g. unemployment and homelessness), especially in the context of prevalent substance use.

Interventions are urgently needed to reduce prescription opioid misuse risk factors, including anxiety and concomitant use of sedatives. However, only a limited number of randomized controlled opioid intervention trials have been conducted. We sought to determine whether an online behavior change/support community, compared to a control Facebook group, could reduce anxiety and opioid misuse among chronic pain patients. 51 high-risk non-cancer chronic pain patients were randomly assigned to either a Harnessing Online Peer Education (HOPE) peer-led online behavior change intervention or a control group (no peer leaders) on Facebook for 12 weeks. Inclusion criteria were: 18 years or older, a UCLA Health System patient, prescribed an opioid for non-cancer chronic pain between 3 and 12 months ago, and a score of ≥9 on the Current Opioid Misuse Measure (COMM) and/or concomitant use of benzodiazepines. Participation in the online community was voluntary. Patients completed baseline and follow-up assessments on Generalized Anxiety Disorder screener (GAD-7), COMM, and frequency of social media discussions about pain and opioid use. Compared to control group participants, intervention participants showed a baseline-to-follow-up decrease in anxiety, and more frequently used social media to discuss pain, prescription opioid use, coping strategies, places to seek help, and alternative therapies for pain. Both groups showed a baseline to follow-up decrease in COMM score. Preliminary results support the use an online community interventions as a low-cost tool to decrease risk for prescription opioid misuse and its complications.

Methamphetamine (MA) triggers neuroinflammation and medications that counteract MA-induced neuroinflammation may reduce MA-induced neurodegeneration and improve neurocognition and treatment outcomes in MA use disorder. We performed a randomized, placebo-controlled trial to determine the safety and efficacy of ibudilast (IBUD), a phosphodiesterase inhibitor that reduces neuroinflammation, for the treatment of MA use disorder. Treatment-seeking volunteers with MA use disorder were randomly assigned to receive 12 weeks of IBUD 50 mg twice daily (N = 64) or placebo (N = 61) with medication management counseling. Participants visited the outpatient research clinic twice weekly to provide urine specimens for drug screens and undergo study assessments. The primary outcome was end of treatment MA-abstinence (EOTA) during weeks 11 and 12 of treatment. Serum IBUID levels were measured for IBUD participants during week 3 of treatment. There was no difference in EOTA for IBUD (14%) versus placebo (16%, p > 0.05). There was no correlation between serum IBUD levels and MA use during treatment and mean IBUD levels for participants with (mean = 51.3, SD = 20.3) and without (mean = 54.7, SD = 33.0, p = 0.70) EOTA. IBUD was well tolerated. IBUD did not facilitate MA abstinence in this outpatient trial. Whether targeting neuroinflammation, either with IBUD in other subgroups of MA users or clinical trial designs, or with other anti-inflammatory medications, is an effective strategy for treating MA use disorder is not clear.

Objective: To examine somatization, mental health, and pain catastrophizing factors as predictors of risk for opioid misuse in patients with chronic non-cancer pain.Methods: Risk for prescription opioid misuse was examined using the Current Opioid Misuse Measure (COMM). Overall, 51 patients were enrolled in the study and completed the baseline survey that assessed anxiety (GAD-7), somatization (PHQ-15), depression (PHQ-9), and pain catastrophizing indicators (PCS).Results: Overall, a high proportion of patients screened positive for anxiety (30%), somatization (73%), depression (43%), and pain catastrophizing subscales (magnification 29%, rumination 29%, and helplessness 18%). Patients who screened positive for anxiety disorder reported a significantly higher COMM score compared to those without symptoms (28.19 vs. 15.11, p < .0001). Patients with depressive symptoms also reported significantly higher COMM score compared to those without depressive symptoms (25.18, vs. 14.69, p = .0007). Those with PCS 'magnification' reported significantly higher COMM score (25.0), compared to those without 'magnification' (16.81; p = .018). Similarly, those with PCS 'rumination' scored higher on the COMM score compared to those without 'rumination' (25.9 vs 17.59, p = .038).Conclusions: These findings underscore the importance of future interventions to address mental health and pain catastrophizing symptoms when treating patients with chronic non-cancer pain for opioid misuse.

Background: Preclinical studies suggest that the non-selective phosphodiesterase inhibitor, Ibudilast (IBUD) may contribute to the treatment of methamphetamine (METH) use disorder through the attenuation of METH-induced inflammatory markers such as adhesion molecules, sICAM-1 and sVCAM-1, and cytokines, IL-6 and TNF-alpha. Objective: The present study aimed to test whether treatment with IBUD can attenuate peripheral markers of inflammation during a METH challenge in an inpatient clinical trial of 11 patients. Methods: This trial followed a randomized, within-subjects crossover design where participants received a METH challenge, during which five participants were treated with placebo then with IBUD, while the remaining six participants were treated with IBUD prior to placebo. Mixed effects regression modeled changes in peripheral markers of inflammation-sICAM-1, sVCAM-1, TNF-alpha, IL-6, MIF, and cathepsin D-by treatment condition, with measurements at baseline, 60 min post-METH infusion, and 360 min post-METH infusion. Results: While on placebo, sICAM-1, sVCAM-1, and cathepsin D significantly increased by 60 min post-METH infusion, while IL-6 significantly increased 360 min post-METH infusion. Treatment with IBUD significantly reduced METH-induced levels of sICAM-1, sVCAM-1, and cathepsin D at 60 min post-METH infusion. Conclusions: Our findings demonstrate that IBUD attenuated acute pro-inflammatory effects of METH administration, which may have implications for treatment of METH use disorder.

Clinicians who work in mental health settings are in an optimal position to treat an alcohol use disorder (AUD) that co-occurs with a primary mental health condition. This tool is a guide to identifying and treating clients with a co-occurring alcohol use disorder in mental health settings with pharmacotherapy and includes a prescriber summary that defines a strategy for prescribing AUD medications in mental health settings.

Aims: Assess whether the Harnessing Online Peer Education (HOPE) social media-based support group can engage patients on opioids at risk for misuse/overdose to discuss risk reduction strategies. Methods: Fifty-one patients on chronic opioid therapy and risk factors for aberrant medication-taking behaviors were randomized to a HOPE intervention or control (Facebook) group. Results: Compared to control group participants, intervention participants had almost 10 times higher posting engagement (n = 411 posts versus 45; 73% versus 52% of participants). Participants discussed coping, pain, medication and non-medication treatments, and other opioid and addiction-related topics. Discussion: Results suggest that a HOPE online community might serve as an effective behavioral intervention tool among chronic pain patients on opioid therapy.

Background: Previous studies have suggested that varenicline, an alpha 4 beta 2 nicotinic receptor partial agonist, and alpha 7 nicotinic receptor full agonist, may be effective for the treatment of methamphetamine (MA) dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. This study aimed to determine if varenicline (1 mg BID) resulted in reduced methamphetamine use compared to placebo among treatment-seeking MA-dependent volunteers. Methods: Treatment-seeking MA-dependent volunteers were randomized to varenicline 1 mg twice daily (n = 27) or placebo (n = 25) and cognitive behavioral therapy for 9 weeks. The primary outcomes were the proportion of participants achieving end-of-treatment-abstinence (EOTA, MA-negative urine specimens during weeks 8 and 9) and the treatment effectiveness score (TES, number of MA-negative urine specimens) for varenicline versus placebo. Results: There was no significant difference in EOTA between varenicline (15%, 4/27) and placebo (20%, 5/25; p = 0.9). There was some suggestion that urinary confirmed medication compliance corresponded with EOTA in the varenicline condition, though it did not reach statistical significance, OR = 1.57 for a 100 ng/ml increase in urine varenicline, p = 0.10, 95% CI (0.99, 3.02). There was no significant difference in mean TES in the varenicline condition (8.6) compared to the placebo condition (8.1), and treatment condition was not a statistically significant predictor of TES, IRR = 1.01, p = 0.9, 95% CI (0.39, 2.70). Conclusions: The results of this study indicate that 1 mg varenicline BID was not an effective treatment for MA dependence among treatment-seeking MA-dependent volunteers.

Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse.