Impact of Nicotine Replacement Therapy Sampling on Cessation-Related Processes.

OBJECTIVES: Smoking prevalence remains high among low-income smokers. Understanding processes (eg, withdrawal, craving, motivation) in early smoking cessation is crucially important for designing effective interventions for this population. METHODS: This is a secondary analysis of a novel, in-session sampling intervention (ie, In Vivo) as compared with standard care behavioral smoking cessation counseling (SC) among community-dwelling low-income smokers (n = 83). This analysis examined the effect of 5 in-session sampling interventions on cessation-related processes and perceived advantages or disadvantages of nicotine replacement therapy (NRT) products over time using daily diaries. RESULTS: The In Vivo treatment had an early positive impact in terms of decreasing withdrawal symptoms and cravings, and increasing perceived advantages to NRT, with moderate to large effect sizes. Results also showed that the treatment effectively reduced withdrawal symptoms and cravings in-session, with small-to-medium and medium-to-large effect sizes, respectively. In-session reduction of withdrawal symptoms and cravings did not occur for the SC group, with the exception of decreased withdrawal symptoms occurring during week 4. The In Vivo treatment did not impact quit goal, desire to quit, abstinence self-efficacy, perceived difficulty in quitting, motivational engagement, or perceived disadvantages to NRT. The In Vivo group reported less daily cigarette use relative to the SC group, in addition to reporting less cigarette use on days they reported greater combination NRT use. CONCLUSIONS: There is preliminary support for this In Vivo treatment over SC in reducing withdrawal, craving, and the number of cigarettes smoked per day, as well as promoting perceived advantages of NRT among low-income smokers.

Psychedelic Microdosing among Young Adults from Southern California.

Despite common depictions in the media, there is little scientific evidence on microdosing psychedelic drugs. We assessed awareness, prevalence, and dosing practices of microdosing psychedelic drugs among young adults 18-22 years old from Southern California (2018-2019). We examined whether sociodemographic factors, personality traits, mental health, or other substance use behaviors were correlated with having ever microdosed. Among 2,396 participants, 293 (12%) had heard of microdosing and 74 (3%) ever microdosed. Among those who had heard of microdosing, 79% correctly defined microdosing as taking an amount of a psychedelic much lower than a standard dose, whereas 15% misperceived microdosing as a standard psychedelic dose. Psilocybin was the most common drug ever microdosed (70%), followed by lysergic acid diethylamide (LSD, 57%). Among those who ever microdosed, ~18% reported using psychoactive doses far higher than would be generally considered a microdose. White race, male/masculine gender identity, bisexual identity, past 6-month other drug use, greater attention deficit/hyperactivity disorder symptoms, mindfulness, and sensation-seeking were positively associated with having ever microdosed in multivariable models. Young adult microdosing merits further attention from scientific and public health professionals to help prevent misperceptions and potential adverse consequences as well as explore its potential therapeutic applications.

Longitudinal associations between psychedelic use and psychotic symptoms in the United States and the United Kingdom.

It has long been speculated that psychedelic use could provoke the onset of psychosis, but there is little evidence to support this conjecture. Using a longitudinal research design with samples representative of the US and UK adult populations with regard to sex, age, and ethnicity (n = 9732), we investigated associations between psychedelic use and change in the number of psychotic symptoms during the two-month study period. In covariate-adjusted regression models, psychedelic use during the study period was not associated with a change in the number of psychotic symptoms unless it interacted with a personal or family history of bipolar disorder, in which case the number of symptoms increased, or with a personal (but not family) history of psychotic disorders, in which case the number of symptoms decreased. Taken together, these findings indicate that psychedelic use may affect psychotic symptoms in individuals with a personal or family history of certain disorders characterized by psychotic symptomatology.

IUPHAR-review: The integration of classic psychedelics into current substance use disorder treatment models.

Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelics with contemporary SUD treatment paradigms.

Longitudinal associations between psychedelic use and meditation practices in the United States and the United Kingdom.

BACKGROUND: Previous research has proposed that there may be potential synergies between psychedelic and meditation interventions, but there are still knowledge gaps that merit further investigation. METHODS: Using a longitudinal observational research design with samples representative of the US and UK adult population with regard to sex, age, and ethnicity (N = 9732), we investigated potential associations between self-reported psychedelic use and meditation practice. RESULTS: The follow-up survey was completed by 7667 respondents (79% retention rate), with 100 respondents reporting psychedelic use during the 2-month study period (1.3% of follow-up respondents). In covariate-adjusted regression models, psychedelic use during the study period was associated with greater increases in the number of days of mindfulness meditation practice in the past week (B = 0.40, p = 0.004). Among those who reported psychedelic use during the study period, covariate-adjusted regression models revealed that the subjective experience of insight during respondents' most intense psychedelic experience in that period was also associated with greater increases in the number of days of mindfulness and loving-kindness or compassion meditation practice in the past week (B = 0.42, p = 0.021; B = 0.38, p = 0.017). Notably, more days of loving-kindness or compassion meditation practice in the past week at baseline was associated with less severe subjective feelings of death or dying during respondents' most intense psychedelic experience in the study period (B = -0.29, p = 0.037). CONCLUSIONS: Psychedelic use might lead to greater engagement with meditation practices such as mindfulness meditation, while meditation practices such as loving-kindness or compassion medication might buffer against certain challenging experiences associated with psychedelic use.

Longitudinal associations between psychedelic use and unusual visual experiences in the United States and the United Kingdom.

BACKGROUND: Whereas findings from case reports and cross-sectional studies suggest that naturalistic psychedelic use may be associated with unusual visual experiences that occur after the acute pharmacological effects have subsided, such findings need to be replicated in longitudinal studies to better understand potential cause-and-effect relationships. AIMS: To investigate longitudinal associations between naturalistic psychedelic use and unusual visual experiences. METHODS: Using a longitudinal observational research design with samples representative of the US and UK adult populations with regard to sex, age, and ethnicity (N = 9732), we investigated the relationship between psychedelic use during the 2-month study period and changes in past-week unusual visual experiences. RESULTS: The follow-up survey was completed by 79% of respondents (n = 7667), with 100 respondents reporting psychedelic use during the 2-month study period (1.3% of those who responded at follow-up). In covariate-adjusted regression models, the results showed that, as hypothesized, psychedelic use during the 2-month study period was associated with greater increases in unusual visual experiences. Notably, there was an interaction between lifetime psychedelic use and psychedelic use during the study period on unusual visual experiences such that those who used psychedelics for the first time reported greater increases in unusual visual experiences. CONCLUSIONS: Psychedelic use may elicit unusual visual experiences that occur after the acute pharmacological effects have subsided, especially among those who have not used psychedelics previously. Future longitudinal studies are warranted to further elucidate these relationships.

5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by reviewing aberrant 5-HT1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT1A receptor agonist properties-and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform activity, suggesting a similarity to electroconvulsive therapy. It is also noted that "reactivations," the sudden re-experiencing of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms in research settings and among naturalistic users are warranted.

Psychedelic use and psychiatric risks.

RATIONALE: Research on psychedelics has recently shown promising results in the treatment of various psychiatric disorders, but relatively little remains known about the psychiatric risks associated with naturalistic use of psychedelics. OBJECTIVE: The objective of the current study was to investigate associations between naturalistic psychedelic use and psychiatric risks. METHODS: Using a sample representative of the US adult population with regard to sex, age, and ethnicity (N=2822), this study investigated associations between lifetime naturalistic psychedelic use, lifetime unusual visual experiences, and past 2-week psychotic symptoms. RESULTS: Among respondents who reported lifetime psychedelic use (n=613), 1.3% reported having been told by a doctor or other medical professional that they had hallucinogen persisting perception disorder. In covariate-adjusted linear regression models, lifetime psychedelic use was associated with more unusual visual experiences at any point across the lifetime, but no association was observed between lifetime psychedelic use and past 2-week psychotic symptoms. There was an interaction between lifetime psychedelic use and family (but not personal) history of psychotic or bipolar disorders on past 2-week psychotic symptoms such that psychotic symptoms were highest among respondents who reported lifetime psychedelic use and a family history of psychotic or bipolar disorders and lowest among those who reported lifetime psychedelic use and no family history of psychotic or bipolar disorders. CONCLUSIONS: Although the results in this study should be interpreted with caution, the findings suggest that lifetime naturalistic use of psychedelics might be associated with more unusual visual experiences across the lifetime, as well as more psychotic symptoms in the past 2 weeks for individuals with a family history of psychotic or bipolar disorders and the reverse for those without such a family history. Future research should distinguish between different psychotic and bipolar disorders and should also utilize other research designs (e.g., longitudinal) and variables (e.g., polygenic risk scores) to better understand potential cause-and-effect relationships.

The relationship between chronic lung disease diagnosis and the susceptibility to e-cigarette use in adults: The mediation effects of psychosocial, cognitive influences, and the moderation effect of physiological factors.

INTRODUCTION: There is a paucity of studies on e-cigarette use among adults with chronic lung disease. In the present study, we aimed to assess whether psychosocial or cognitive factors elucidate the relationship between chronic lung disease (CLD) and susceptibility to e-cigarette use and whether the relationship between CLD and e-cigarette use is conditional on the presence of respiratory symptoms. METHODS: We recruited adults aged ≥18 years in Alabama with CLD from university medical clinics (n=140) and individuals without CLD (n=123 as a reference group). Information on sociodemographics, susceptibility to e-cigarette use, psychosocial factors, and cognitive factors were collected. Mediation analysis was used to assess whether the psychosocial factors or cognitive factors explained the association between CLD and susceptibility to using e-cigarettes, and moderation analysis was conducted to determine if respiratory factors would change the association between CLD and susceptibility to e-cigarette use. RESULTS: Psychosocial factors (stress, depression, anxiety) and e-cigarette positive expectancy were notably high among individuals with CLD. Having CLD was associated with a lower likelihood of susceptibility to e-cigarette use. Higher levels of stress, being a smoker, boredom, taste/sensorimotor manipulation, and social facilitation were associated with higher odds of susceptibility to using e-cigarettes among individuals with CLD. Mediation analysis indicated a statistically significant indirect effect of CLD on the susceptibility to using e-cigarettes through stress and boredom reduction. We did not find a statistically significant interaction between CLD and respiratory symptoms affecting susceptibility to using e-cigarettes. CONCLUSIONS: Individuals with CLD often exhibit stress, depression, and a positive view of e-cigarettes but are generally less inclined to use them. Stress, smoking habits, boredom, taste, and social influence can increase their susceptibility to e-cigarette use. Our findings call for further exploration to evaluate the temporal relationship between CLD status, psychosocial factors, cognitive factors, and susceptibility to using e-cigarettes. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov, on 5 November 2019. Identifier: NCT04151784.

Classic psychedelic use and current meditation practice.

Objectives: Previous research has investigated potential synergies between classic psychedelics and meditation practice, but relatively little remains known about the relationship between classic psychedelic experiences and engagement with meditation practice.The purpose of this study was to investigate associations between classic psychedelic experiences and engagement with two popular types of meditation: mindfulness meditation and loving-kindness or compassion meditation. Methods: This retrospective, population-based observational study included 2,822 respondents aged 18 years or older in the United States. Using covariate-adjusted regression models, this study examined associations of classic psychedelic experiences with current practice of mindfulness meditation and loving-kindness or compassion meditation. Results: In covariate-adjusted regression models, lifetime classic psychedelic use was associated with a higher frequency of current mindfulness meditation practice but not current loving-kindness or compassion meditation practice. Both psychological insight and "ego dissolution" were associated with a higher frequency of current mindfulness meditation practice and current loving-kindness or compassion meditation practice. Notably, when psychological insight and "ego dissolution" were entered into the regression model simultaneously, only greater psychological insight was associated with having a higher frequency of current mindfulness meditation practice and current loving-kindness or compassion meditation practice. Conclusion: Although the findings in this study cannot demonstrate causality, they suggest that classic psychedelic experiences may exert a positive effect on the cultivation and maintenance of health-related behaviors such as regular meditation practice, with psychological insight appearing to be a stronger predictor than "ego dissolution." Preregistration: This study was not preregistered.

Examining Racial/Ethnic and Income Disparities on Tobacco Product Use Among US Adults Within Wave 5 of the PATH Study.

OBJECTIVE: The aim of this study was to examine the interactions between race/ethnicity and income across different types of tobacco products. METHODS: The prevalence of past 30-day use of cigarettes, traditional cigars, cigarillos, filtered little cigars, and electronic nicotine delivery systems (ENDS) among adults was examined by race/ethnicity and income levels based on wave 5 (2018-2019) data of the Population Assessment of Tobacco and Health study. RESULTS: Multivariate analysis across race/ethnicity and income showed that, although non-Hispanic Blacks (NHBs) were significantly more than likely to smoke cigarettes than non-Hispanic Whites (NHWs) at low- and high-income levels, such disparity only applied to low-income Hispanics compared with low-income NHWs. NHBs were significantly more likely to smoke traditional cigars, cigarillos, and filtered little cigars than NHWs at low and high incomes. No differences were found between Hispanics and NHWs with regard to traditional cigars and cigarillos. However, low-income Hispanics were significantly less likely to smoke filtered little cigars than NHWs, whereas high-income Hispanics were more likely to do so than NHWs. With regard to ENDS, significant differences were only found at the low-income bracket with NHBs and Hispanics being less likely to smoke these products than NHWs. CONCLUSIONS: Our findings highlight significant interactions between race/ethnicity and income in the use of tobacco products, suggesting that income should be taken into account when designing interventions targeting different racial/ethnic groups.

An Open-label Pilot Study of NicoBloc as a Novel Smoking Cessation Intervention.

INTRODUCTION: NicoBloc is a viscous fluid applied to the cigarette filter designed to block tar and nicotine. This novel and understudied smoking cessation device presents a nonpharmacological means for smokers to gradually reduce nicotine and tar content while continuing to smoke their preferred brand of cigarette. This pilot study aimed to assess the feasibility, acceptability, and initial efficacy of NicoBloc as compared with nicotine replacement therapy (nicotine lozenge). METHODS: A community sample of predominately Black smokers (N = 45; 66.7% Black) were randomized to receive NicoBloc or nicotine lozenge. Both groups engaged in 4 weeks of smoking cessation therapy followed by 2 months of independent usage with monthly check-ins to assess medication adherence. The intervention lasted 12 weeks, and the study concluded with a 1-month postintervention follow-up visit (week 16). RESULTS: NicoBloc was comparable with nicotine lozenge in smoking reduction, feasibility, symptom adverse effects, and reported acceptability at week 16. Participants in the lozenge group endorsed higher treatment satisfaction ratings during the intervention and lower cigarette dependence. Adherence to NicoBloc was superior throughout the study. CONCLUSION: NicoBloc was feasible and acceptable to community smokers. NicoBloc presents a unique, nonpharmacological intervention. Future research is needed to examine whether this intervention may be most effective in subpopulations where pharmacological approaches are restricted or in combination with established pharmacological methods such as nicotine replacement therapy.

A Qualitative Analysis of First-Hand Accounts of Diphenhydramine Misuse Available on YouTube.

Deliriants are the least studied class of hallucinogens and display noticeable subjective effects, including dysphoria, hallucinations, and substantial alterations in thought. High doses of diphenhydramine (DPH), an over-the-counter antihistamine medication, can produce deliriant effects due to secondary anticholinergic activity. We sought to characterize the subjective experiences produced by DPH misuse to better understand deliriants more broadly and the context under which DPH misuse occurs. To conduct our analysis, 32 first-hand accounts of DPH misuse publicly available in YouTube videos were analyzed using inductive thematic analysis. Video makers discussed alterations in most sensory modalities, confusion, and a tendency for strongly unpleasant experiences. Occasionally, video makers reported positive effects, although these were rare and often overshadowed by negative aspects of the experience. Video makers frequently warned against misusing DPH, and these individuals occasionally reported adverse post-acute effects. Despite the prevalence of adverse experiences, patterns of repeated misuse were sometimes discussed. Motives for misusing DPH, when mentioned, included accessibility, affordability, and legality. Overall, findings suggest DPH misuse can produce substantial psychoactive effects that are often distressing and share some phenomenological overlap with experiences produced by psychosis.

Adapting psychedelic medicine for headache and chronic pain disorders.

INTRODUCTION: While the majority of current research and development surrounds depression, demoralization, and substance use disorders, there are numerous reports of psychedelics having beneficial effects in other branches of medicine, including for headache disorders and chronic pain. AREAS COVERED: This perspective reviews conventional forms of treatment for headache and other chronic pain disorders and describes historical, recent, and ongoing investigations of the therapeutic effects of psychedelics in these disorders. The first two clinical trials of psilocybin in headache disorders and recent case reports of psilocybin mushroom self-administration in chronic pain patients are described. This perspective highlights several factors related to the application of psychedelics in chronic pain disorders, comparing this with the standard psychedelic-assisted psychotherapy model of treatment. EXPERT OPINION: When faced with a more constricted view of psychedelic medicine that features larger doses, underscores subjective effects in the mediation of therapeutic outcomes, and requires adjunctive psychotherapy to ensure safety and efficacy, the application of psychedelics in headache and chronic pain disorders may face challenges. It will be important to allow for flexibility and adaptation in protocols to evaluate different treatment paradigms, mechanisms of action, and the range of pharmacologic and extra-pharmacologic factors that affect psychedelic treatment outcomes.

Altered states of leadership: mindfulness meditation, psychedelic use, and leadership development.

Background: Previous research suggests that mindfulness meditation and psychedelic substances show promise as mental health interventions, but relatively little remains known about their potential impact on leadership outcomes. Aims: This study aimed to investigate if and how mindfulness meditation and psychedelic use may impact leadership among respondents with a management position as their primary role at work. Methods: Using samples representative of the US and UK adult populations with regard to sex, age, and ethnicity, this study used quantitative and qualitative methods to examine if and how mindfulness meditation and psychedelic use may impact leadership. Results: Among respondents with a management position as their primary role at work (n = 3,150), 1,373 reported having tried mindfulness meditation and 559 reported having tried psychedelics. In covariate-adjusted regression analyses, both lifetime number of hours of mindfulness meditation practice and greater psychological insight during respondents' most intense psychedelic experience were associated with describing a positive impact on leadership (ORs = 2.33, 3.49; ps < 0.001), while qualitative analyses revealed nuances in the type of impacts mindfulness meditation and psychedelic use had on leadership. There were several subthemes (e.g., focus, creativity, patience, empathy, compassion) that were frequently reported with both mindfulness meditation and psychedelic use. There were also unique subthemes that were more commonly reported with mindfulness meditation (e.g., improved sleep, stress reduction, calming effects) and psychedelic use (e.g., greater self-understanding, less hierarchical attitudes toward colleagues, positive changes in interpersonal attitudes and behaviors), respectively. Conclusion: Although causality cannot be inferred due to the research design, the findings in this study suggest potential complementary effects of mindfulness meditation and psychedelic use on leadership, which could inspire new approaches in leadership development.

Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs.

Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Relationship Between Chronic Lung Disease Diagnosis and Susceptibility to E-Cigarette Use in Adults.

BACKGROUND: Electronic cigarettes (e-cigarettes) are known to cause adverse pulmonary effects, yet paradoxically, the prevalence of e-cigarette use has increased among individuals with chronic lung disease. We assessed the relationship between chronic lung disease and the susceptibility to e-cigarette use in adults and determined if specific behavioral, social, and environmental factors influence this relationship. METHODS: We enrolled adults age ≥ 18 y in Alabama with chronic lung disease from university medical clinics (n = 140) and individuals without chronic lung disease (n = 123, reference group) from January 2020-March 2021. A cross-sectional design was used where we administered questionnaires to collect sociodemographic information and assessed susceptibility to e-cigarette use, exposure to social and environmental factors (ie, advertisements, warning labels, special prices, others' e-cigarette vapors, use of an e-cigarette by others in the home, and visiting a web site or online discussion), and behavioral factors (ie, alcohol and cannabis use). Moderation analyses were conducted to determine if any of these factors would modify the association between chronic lung disease and susceptibility to e-cigarette use. RESULTS: Susceptibility to e-cigarette use was higher among adults without chronic lung disease than among those with chronic lung disease. Noticing e-cigarette warning labels and visiting a web site or online discussion about e-cigarettes were significantly associated with an increased likelihood of susceptibility to using e-cigarettes in both groups. Exposure to e-cigarette vapor from close contacts, special pricing, living with someone who uses e-cigarettes, and cannabis use were significantly associated with an increased likelihood of susceptibility to e-cigarette use in individuals without chronic lung disease. However, our analyses did not indicate a statistically significant interaction between chronic lung disease and any social, environmental, or behavioral factors on susceptibility to e-cigarette use. CONCLUSIONS: Individuals without chronic lung disease were more susceptible to e-cigarette use than those with chronic lung disease. Although the prevalence of some behavioral and environmental factors differed among individuals with and without chronic lung disease, these factors did not moderate the association between chronic lung disease and susceptibility to e-cigarette use. Longitudinal investigations are warranted to better test the temporal relationships between chronic lung disease, substance use, social and environmental factors, and the susceptibility to e-cigarette use among individuals with chronic lung disease to identify prevention strategies for this population.

Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics.

Previous studies have investigated challenging, difficult, or distressing classic psychedelic experiences, but little is known about the prevalence and associations of such experiences. Using nationally representative data of the US adult population (N = 2822), this study examined the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics, in a subsample of respondents who reported lifetime classic psychedelic use (n = 613). Of the 613 respondents who reported lifetime classic psychedelic use, the majority of them (59.1 %) had never had a challenging, difficult, or distressing experience using a classic psychedelic, but 8.9 % of respondents reported functional impairment that lasted longer than one day as a result of such experiences. Notably, 2.6 % reported seeking medical, psychiatric, or psychological assistance in the days or weeks following their most challenging, difficult, or distressing classic psychedelic experience. In covariate-adjusted regression models, co-use of lithium, co-use of other mood stabilizers, and six set and setting variables (no preparation, disagreeable physical environment, negative mindset, no psychological support, dose was too large, major life event prior to experience) were associated with the degree of difficulty; and co-use of lithium, co-use of other mood stabilizers, and three set and setting variables (negative mindset, no psychological support, major life event prior to experience) were associated with overall risk of harm. In summary, this study provides insight into the prevalence and associations of challenging, difficult, or distressing classic psychedelic experiences. The findings broadly correspond with findings from previous studies and can inform harm reduction efforts and future experimental research designs.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.