Increased global integration in the brain after psilocybin therapy for depression.

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

Associations between lifetime classic psychedelic use and markers of physical health.

BACKGROUND: In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence physical health. AIMS: The purpose of the present study was to investigate the associations between lifetime classic psychedelic use and markers of physical health. METHODS: Using data from the National Survey on Drug Use and Health (2015-2018) with 171,766 (unweighted) adults aged 18 or above in the United States, the current study examined the associations between lifetime classic psychedelic use and three markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months) while controlling for a range of covariates. RESULTS: Respondents who reported having tried a classic psychedelic at least once in their lifetime had significantly higher odds of greater self-reported overall health and significantly lower odds of being overweight or obese versus having a normal weight. The association between lifetime classic psychedelic use and having a heart condition and/or cancer in the past 12 months approached conventional levels of significance, with lower odds of having a heart condition and/or cancer in the past 12 months for respondents who had tried a classic psychedelic at least once. CONCLUSION: The results of the present study suggest that classic psychedelics may be beneficial to physical health. Future research should investigate the causal effects of classic psychedelics on physical health and evaluate possible mechanisms.

Prevalence and epidemiological associates of novel psychedelic use in the United States adult population.

BACKGROUND: Novel psychedelics approximate classic psychedelics, but unlike classic psychedelics, novel psychedelics have been used by humans for a shorter period of time, with fewer data available on these substances. AIMS: The purpose of this study was to determine the prevalence of novel psychedelic use and the associations of novel psychedelic use with mental health outcomes. METHODS: We estimated the prevalence of self-reported, write-in lifetime novel psychedelic use and evaluated the associations of novel psychedelic use with psychosocial characteristics, past month psychological distress, and past year suicidality among adult respondents pooled from years 2008-2016 of the National Survey on Drug Use and Health (weighted n=234,914,788). RESULTS: A fraction (weighted n=273,720; 0.12%) reported lifetime novel psychedelic use. This cohort tended to be younger, male, and White, have greater educational attainment but less income, be more likely to have never been married, engage in self-reported risky behavior, and report lifetime illicit use of other drugs, particularly classic psychedelics (96.9%). (2-(4-Bromo-2,5-dimethoxyphenyl)ethanamine) (2C-B) (30.01%), (2,5-dimethoxy-4-iodophenethylamine) (2C-I) (23.9%), and (1-(2,5-dimethoxy-4-ethylphenyl)-2-aminoethane) (2C-E) (14.8%) accounted for the majority of lifetime novel psychedelic use. Although lifetime novel psychedelic use was not associated with psychological distress or suicidality compared to no lifetime novel psychedelic use or classic psychedelic use, relative to lifetime use of classic psychedelics but not novel psychedelics, lifetime novel psychedelic use was associated with a greater likelihood of past year suicidal thinking (adjusted Odds Ratio (aOR)=1.4 (1.1-1.9)) and past year suicidal planning (aOR=1.6 (1.1-2.4)). CONCLUSION: Novel psychedelics may differ from classic psychedelics in meaningful ways, though additional, directed research is needed.

Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine, Tryptamine, and Lysergamide Psychedelics.

INTRODUCTION: The majority of contemporary psychedelic research has focused on ayahuasca, lysergic acid diethylamide, and psilocybin, though there are hundreds of novel psychedelic compounds that may have clinical utility. The purpose of the present study was to evaluate the therapeutic potential of classic and novel phenethylamine, tryptamine, and lysergamide psychedelics via a large, nationally representative population-based survey. METHODS: We tested the unique associations of lifetime classic and novel phenethylamine, tryptamine, and lysergamide psychedelics with past month psychological distress and past year suicidality among respondents pooled from years 2008-2017 of the National Survey on Drug Use and Health (weighted N = 260,964,827). RESULTS: Lifetime classic tryptamine use was associated with a decreased odds of past month psychological distress [aOR = 0.76; (0.69-0.83)] and past year suicidal thinking [aOR = 0.79; (0.72-0.87)]. Lifetime novel phenethylamine use, on the other hand, was associated with an increased odds of past year suicidal thinking [aOR = 1.44; (1.06-1.95)] and past year suicidal planning [aOR = 1.60; (1.06-2.41)]. No other significant associations were found. DISCUSSION AND CONCLUSIONS: These findings, which may be driven by differences in pharmacodynamics, suggest that classic tryptamines may hold the greatest therapeutic potential of the psychedelics, whereas novel phenethylamines may pose risk for harm. The present findings thus support continued research on the clinical application of classic tryptamines. Though the current results caution against the clinical utility of novel phenethylamines, further study of these and other novel psychedelic substances is nonetheless warranted to better understand their potential application.