Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Past Is Prologue: Ethical Issues in Pediatric Psychedelics Research and Treatment.

Recent clinical trials of psychedelic drugs aim to treat a range of psychiatric conditions in adults. MDMA and psilocybin administered with psychotherapy have received FDA designation as "breakthrough therapies" for post-traumatic stress disorder (PTSD) and treatment-resistant depression (TRD) respectively. Given the potential benefit for minors burdened with many of the same disorders, calls to expand experimentation to minors are inevitable. This essay examines psychedelic research conducted on children from 1959 to 1974, highlighting methodological and ethical flaws. It provides ethics and policy recommendations for psychedelics research involving children and adolescents, including recognizing that the psychedelic experience is an ineffable one that makes informed proxy consent for parents, guardians, and others especially challenging. Psychedelic experiences are associated with novel benefits and risks, such as significant personality changes, shifts in fundamental values, and possible re-exposure to traumatic memories. These effects may alter the process of personality development in minors. Recommendations for ethically sound psychedelics research in minors include strict adherence to eligibility criteria, including a comprehensive family and individual psychiatric, substance use, and trauma history. An age-appropriate assent process that includes considerations related to the use of therapeutic touch should be developed. In addition, oversight by data safety monitoring boards and patient and family advocates, coupled with the adoption of pharmacoequity best practices, will help to ensure safety and fairness of psychedelics research in children.

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.

BACKGROUND: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes. AIMS: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin. METHODS: This randomized, waiting-list controlled study enrolled 27 patients aged 21-75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed through 12 months following their second dose. RESULTS: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression. CONCLUSIONS: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

Psilocybin use is associated with lowered odds of crime arrests in US adults: A replication and extension.

BACKGROUND: The United States boasts the largest prison population in the world, conferring significant direct and indirect costs (e.g. lost wages for the incarcerated, increased morbidity/mortality, etc.) to society. Recidivism rates are high for the imprisoned and most interventions to reduce criminality are minimally effective. Thus, in addition to the need for criminal justice reform, there is a need to better understand factors linked to lowered criminal behavior. AIM: The aim of this study was to assess the relationships between the use of classic psychedelic substances (psilocybin, LSD, peyote, and mescaline) and past year arrests for various crimes (i.e. property, violence, alcohol and substance use, miscellaneous crimes). METHODS: This study used nationally representative data from The National Survey on Drug Use and Health (NSDUH) (2015-2019) (N = 211,549) to test the aforementioned associations. RESULTS: Lifetime psilocybin use was associated with lowered odds of seven of 11 past year arrest variables (adjusted odds ratio (aOR) range = 0.30-0.73). Peyote was associated with reduced odds of motor vehicle theft (aOR = 0.30) and driving under the influence (aOR = 0.52), and mescaline was associated with reduced odds of drug possession/sale (aOR = 0.51). Virtually all other substances either shared no relationship to our outcomes or conferred higher odds of arrest. CONCLUSION: This study suggests that use of classic psychedelic substances is associated with lowered odds of crime arrests. Future research should explore whether causal factors and/or third variable factors (e.g. personality, political orientation) underlie the relationship between classic psychedelic use and reduced criminal behavior.

The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation.

BACKGROUND: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin's effects on cognitive function have not been widely or systematically studied. AIM: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. METHODS: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support - each participant having an assigned, dedicated therapist available throughout the session. RESULTS: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. CONCLUSIONS: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. CLINICAL TRIAL REGISTRATION: EudraCT (https://www.clinicaltrialsregister.eu/) number: 2018-000978-30.

MDMA/ecstasy use and psilocybin use are associated with lowered odds of psychological distress and suicidal thoughts in a sample of US adults.

BACKGROUND: Suicide is one of the leading causes of death worldwide and rates within the United States have risen over the past two decades. Hence, there is a critical need for novel tools to treat suicidal ideation and related mental health conditions. 3,4-Methylenedioxymethamphetamine (MDMA)/ecstasy and classic psychedelics may be two such tools. AIMS: The aim of this study was to assess non-causal associations between MDMA/ecstasy and classic psychedelic use and psychological distress and suicide risk. METHODS: In this study, we examined the aforementioned associations among 484,732 adult participants in the National Survey on Drug Use and Health (2008-2019). RESULTS: Lifetime MDMA/ecstasy use was associated with reduced odds of past year suicidal thinking (10% reduced odds; odds ratio (OR) = 0.90; 95% confidence interval, CI = (0.84-0.97); p < 0.01) and past year suicidal planning (OR = 0.88; 95% CI = (0.78-0.99); p < 0.05). Furthermore, lifetime psilocybin use was associated with reduced odds of past month psychological distress (OR = 0.78; 95% CI = (0.73-0.84); p < 0.001) and past year suicidal thinking (OR = 0.90; 95% CI = (0.83-0.96); p < 0.01). Finally, lysergic acid diethylamide (LSD) was associated with increased odds of past year suicidal thinking (OR = 1.07; 95% CI = (1.00-1.15); p < 0.05). CONCLUSION: MDMA/ecstasy and psilocybin use are associated with reduced odds of suicidal thinking and related outcomes-though experimental studies are needed to determine whether these associations are causal. These findings call for more research into the efficacy of MDMA/ecstasy and classic psychedelics for treating psychological distress and suicidal thoughts and behaviors, and for updated drug legislation that allows for further investigation into these substances.

Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes.

BACKGROUND: Depression is a major mental health issue worldwide, with high rates of chronicity and non-recovery associated with the condition. Existing treatments such as antidepressant medication and psychological treatments have modest effectiveness, suggesting the need for alternative interventions. AIM: The aim of this study was to examine the relationships between MDMA (3,4-methylenedioxymethamphetamine)/ecstasy and psilocybin use and major depressive episodes (MDEs). METHODS: This observational study used data from a large (N = 213,437) nationally representative sample of US adults to test the association of lifetime use of MDMA/ecstasy, psilocybin and other classic psychedelics (lysergic acid diethylamide (LSD), peyote, mescaline), other illegal substances (e.g. cocaine, phencyclidine (PCP)), and legal/medicinal substances of misuse (e.g. pain relievers, tranquilizers) with lifetime, past year, and past year severe MDEs. RESULTS: Results revealed that lifetime MDMA/ecstasy use was associated with significantly lowered odds of a lifetime MDE (adjusted odds ratio (aOR) = 0.84; p < 0.001), past year MDE (aOR = 0.84; p < 0.001), and past year severe MDE (aOR = 0.82; p < 0.001). Psilocybin was associated with significantly lowered odds of a past year MDE (aOR = 0.90; p < 0.05) and past year severe MDE (aOR = 0.87; p < 0.05). All other substances either shared no relationship with a MDE or conferred increased odds of an MDE. CONCLUSIONS: These results suggest that MDMA/ecstasy and psilocybin use is associated with lower risk of depression. Experimental studies are needed to test whether there is a causal association between use of these compounds and the alleviation of depressive symptoms.

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals.

BACKGROUND: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. AIM: Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. METHODS: Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. RESULTS: Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen's d = -1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months (r = -0.65). CONCLUSIONS: These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic 'afterglow' period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.

Psychedelics and health behaviour change.

Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.

Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention.

BACKGROUND: Microdosing psychedelics is the practice of taking small, sub-hallucinogenic doses of lysergic acid diethylamide or psilocybin-containing mushrooms. Despite its surging popularity, little is known about the specific intentions to start microdosing and the effects of this practice. AIMS: First, we aimed to replicate previous findings regarding the subjective benefits and challenges reported for microdosing. Second, we assessed whether people who microdose test their substances before consumption. Third, we examined whether having an approach-intention to microdosing was predictive of more reported benefits. METHODS: The Global Drug Survey runs the world's largest online drug survey. Participants who reported last year use of lysergic acid diethylamide or psilocybin in the Global Drug Survey 2019 were offered the opportunity to answer a sub-section on microdosing. RESULTS: Data from 6753 people who reported microdosing at least once in the last 12 months were used for analyses. Our results suggest a partial replication of previously reported benefits and challenges among the present sample often reporting enhanced mood, creativity, focus and sociability. Counter to our prediction, the most common challenge participants associated with microdosing was 'None'. As predicted, most participants reported not testing their substances. Counter to our hypothesis, approach-intention - microdosing to approach a desired goal - predicted less rather than more benefits. We discuss alternate frameworks that may better capture the reasons people microdose. CONCLUSION: Our results suggest the perceived benefits associated with microdosing greatly outweigh the challenges. Microdosing may have utility for a variety of uses while having minimal side effects. Double-blind, placebo-controlled experiments are required to substantiate these reports.

Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study.

BACKGROUND: Microdoses of psychedelics (i.e. a sub-hallucinogenic dose taken every third day) can reduce symptoms of depression, anxiety and stress according to anecdotal reports and observational studies. Research with medium to high doses of psilocybin points towards potential underlying mechanisms, including the modulation of emotion and interoceptive processing. AIMS: In this preregistered study, we investigated whether psilocybin microdoses alter self-reported interoceptive awareness and whether repeated microdosing over 3 weeks modulates emotion processing and reduces symptoms of anxiety and depression. METHODS: We used a double-blind, placebo-controlled, within-subject crossover design. Participants completed the Multidimensional Assessment of Interoceptive Awareness Questionnaire 1½ h after self-administering their second dose (or placebo), and the emotional go/no-go task and the shortened Depression Anxiety Stress Scale 1½ h after self-administering their seventh dose. RESULTS: Our confirmatory analyses revealed that psilocybin microdosing did not affect emotion processing or symptoms of anxiety and depression compared with placebo. Our exploratory analyses revealed that psilocybin microdosing did not affect self-reported interoceptive awareness, that symptoms of depression and stress were significantly reduced in the first block compared with baseline, that participants broke blind in the second block and that there was no effect of expectations. Further research in a substance-naïve population with clinical range anxiety and depressive symptoms is needed to substantiate the potential beneficial effects of microdosing.

Adults who microdose psychedelics report health related motivations and lower levels of anxiety and depression compared to non-microdosers.

The use of psychedelic substances at sub-sensorium 'microdoses', has gained popular academic interest for reported positive effects on wellness and cognition. The present study describes microdosing practices, motivations and mental health among a sample of self-selected microdosers (n = 4050) and non-microdosers (n = 4653) via a mobile application. Psilocybin was the most commonly used microdose substances in our sample (85%) and we identified diverse microdose practices with regard to dosage, frequency, and the practice of stacking which involves combining psilocybin with non-psychedelic substances such as Lion's Mane mushrooms, chocolate, and niacin. Microdosers were generally similar to non-microdosing controls with regard to demographics, but were more likely to report a history of mental health concerns. Among individuals reporting mental health concerns, microdosers exhibited lower levels of depression, anxiety, and stress across gender. Health and wellness-related motives were the most prominent motives across microdosers in general, and were more prominent among females and among individuals who reported mental health concerns. Our results indicate health and wellness motives and perceived mental health benefits among microdosers, and highlight the need for further research into the mental health consequences of microdosing including studies with rigorous longitudinal designs.

Blinding and expectancy confounds in psychedelic randomized controlled trials.

Introduction: There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat several mental health disorders, with a growing number of randomized controlled trials (RCTs) being conducted to investigate the therapeutic effectiveness of psychedelics.Areas covered: We review previous literature on expectancy effects and blinding in the context of psychedelic RCTs - literature which strongly suggest that psychedelic RCTs might be confounded by de-blinding and expectancy. We conduct systematic reviews of psychedelic RCTs using Medline, PsychInfo and EMBASE (Jan 1990 - Nov 2020) and show that currently reported psychedelic RCTs have generally not reported pre-trial expectancy, nor the success of blinding procedures.Expert opinion: While psychedelic RCTs have generally shown promising results, with large effect sizes reported, we argue that treatment effect sizes in psychedelic RCTs are likely over-estimated due to de-blinding of participants and high levels of response expectancy. We suggest that psychedelic RCTs should routinely measure de-blinding and expectancy. Careful attention should be paid to clinical trial design and the instructions given to participants to allow these confounds to be reduced, estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs.

Spontaneous and deliberate creative cognition during and after psilocybin exposure.

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Dose-response relationships of psilocybin-induced subjective experiences in humans.

BACKGROUND: Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. AIM: Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. METHOD: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. RESULTS: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. CONCLUSION: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.

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.

Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches.

BACKGROUND: Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. AIMS: The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. METHODS: We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30 mg/70 kg (n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n = 103). RESULTS: In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. CONCLUSIONS: These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.

Use and abuse of dissociative and psychedelic drugs in adolescence.

Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans.

BACKGROUND: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. AIMS: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. METHOD: Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. RESULTS: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. CONCLUSION: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Development and validation of an LC-MS/MS method for the bioanalysis of psilocybin's main metabolites, psilocin and 4-hydroxyindole-3-acetic acid, in human plasma.

Psilocin is the active metabolite of psilocybin, a serotonergic psychedelic substance. It is used recreationally and investigated in substance-assisted psychotherapy. The pharmacokinetic properties of psilocin are only partially characterized. Therefore, we developed and validated a rapid LC-MS/MS method to quantify psilocin and its metabolite 4-hydroxyindole-3-acetic acid (4-HIAA) in human plasma. Plasma samples were processed by protein precipitation using methanol. The injected sample was mixed with water in front of a C18 analytical column to increase retention of the analytes. Psilocin and 4-HIAA were detected by multiple reaction monitoring (MRM) in positive and negative electrospray ionisation mode, respectively. An inter-assay accuracy of 100-109% and precision of ≤8.7% was recorded over three validation runs. The recovery was near to complete (≥94.7%) and importantly, consistent over different concentration levels and plasma batches (CV%: ≤4.1%). The plasma matrix caused negligible ion suppression and endogenous interferences could be separated from the analytes. Psilocin and 4-HIAA plasma samples could be thawed and re-frozen for three cycles, kept at room temperature for 8 h or 1 month at -20 °C without showing degradation (≤10%). The linear range (R ≥ 0.998) of the method covered plasma concentrations observed in humans following a common therapeutic oral dose of 25 mg psilocybin and was therefore able to assess the pharmacokinetics of psilocin and 4-HIAA. The LC-MS/MS method was convenient and reliable for measuring psilocin and 4-HIAA in plasma and will facilitate the clinical development of psilocybin.