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Background and Aims: Lysergic acid diethylamide (LSD) and psilocybin are used as recreational drugs, and there is renewed interest in their clinical use. The current study aimed to (1) determine the circumstances of death and case characteristics of LSD- and psilocybin-related death in Australia, 2000-23; and (2) determine the toxicological profile and major autopsy findings of these cases., Methods: This was a retrospective exploratory study of all cases of LSD- and psilocybin-related death in Australia, 2000-23, retrieved from the National Coronial Information System., Results: A total of 43 cases were identified: 33 LSD and 10 psilocybin. The median ages were 24 years [interquartile range (IQR) = 13, range = 16-53] (LSD) and 26 years (IQR = 18.5, range = 20-58) (psilocybin), and fewer than five cases were female. The most common circumstance of death among both groups was traumatic accident (LSD 36.4%, psilocybin 40.0%). There were 12 cases of self-harm, all of which involved LSD, all by physical means. In a fifth, death was attributed to multiple drug toxicity (LSD 18.2%, psilocybin 20.0%). In one case, death was attributed solely to LSD toxicity, while in a further two cases death was attributed to a cardiovascular event following LSD consumption (one LSD only, one multiple drug toxicity). In four psilocybin cases, the cause of death was undetermined. The most common clinical presentation was severe agitation (LSD 27.3%, psilocybin 20.0%). Median blood concentrations were LSD 0.8 μg/l (IQR = 1.7, range = 0.1-3), psilocin 20 μg/l (IQR = 53.5, range = 6-83). LSD was the only drug present in 25.0% of LSD cases and psilocybin in 20.0% of psilocybin cases. Pre-existing organ pathology was uncommon., Conclusions: Lysergic acid diethylamide (LSD)- and psilocybin-related death in Australia from 2000 to 2023 was primarily due to traumatic injury, whether through accident or self-harm. Cases of acute toxic reactions that were attributed solely to LSD were rare., (© 2024 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Few epidemiological studies have focused on seasonal variation in the use of common psychedelics and party drugs among nightclub and festival attendees, typically those who attend electronic dance music (EDM) events. We sought to determine whether the use of different drug types varies seasonally within this population. Across 15 seasons from summer 2017 through fall 2022, we surveyed 3,935 adults entering randomly selected nightclubs and festivals in New York City regarding their past-month use of cocaine, MDMA (3,4-methylenedioxymethamphetamine, commonly known as ecstasy), lysergic acid diethylamide (LSD), psilocybin (shrooms), and ketamine. Multivariable models were used to compare adjusted odds ratios for drug use within each season with the grand mean of combined seasons. Summer was associated with higher odds for use of LSD (aOR 2.72; 95% CI, 1.88-3.93) and psilocybin (aOR 1.65; CI, 1.12-2.43), independent of increases in psilocybin use over time ( p < .001). A significant increase in use of ketamine ( p  = .014) and significant decreases in use of cocaine ( p  = .002) and ecstasy ( p  = .002) were found across time, but multivariable models did not detect seasonal variations. Summer is a risk factor for use of common psychedelics among people who attend EDM events. Therefore, the summer months may be the best time to disseminate information about harm reduction for psychedelic drug users.

Lysergic acid diethylamide (LSD) is a synthetic psychedelic compound with potential therapeutic value for psychiatric disorders. This study aims to establish Caenorhabditis elegans as an in vivo model for examining LSD's effects on locomotor behavior. Our results demonstrate that LSD is absorbed by C. elegans and that the acute treatment reduces animal speed, similar to the role of endogenous serotonin. This response is mediated in part by the serotonergic receptors SER-1 and SER-4. Our findings highlight the potential of this nematode as a new experimental model in psychedelic research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Taking regular low doses of psychedelic drugs (microdosing) is a practice that has drawn recent scientific and media attention for its potential psychotherapeutic effects. Yet, controlled studies evaluating this practice have lagged. Here, we review recent evidence focusing on studies that were conducted with rigorous experimental control. Studies conducted under laboratory settings using double-blind placebo-controlled procedures and investigator-supplied drug were compiled. The review includes demographic characteristics of participants and dependent measures such as physiological, behavioral, and subjective effects of the drugs. Review criteria were met by 14 studies, all of which involved acute or repeated low (5-20 μg) doses of lysergic acid diethylamide (LSD). Acute microdoses of LSD dose-dependently altered blood pressure, sleep, neural connectivity, social cognition, mood, and perception of pain and time. Perceptible drug effects were reported at doses of 10 to 20 μg but not 5 μg. No serious adverse effects were reported. Repeated doses of LSD did not alter mood or cognition on any of the measures studied. The findings suggest that low doses of LSD are safe and produce acute behavioral and neural effects in healthy adults. Further studies are warranted to extend these findings to patient samples and to other psychedelic drugs and to investigate microdosing as a potential pharmacological treatment for psychiatric disorders., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Though microdosing psychedelics has become increasingly popular, its long-term effects on cardiac health remain unknown. Microdosing most commonly involves ingesting sub-threshold doses of lysergic acid diethylamide (LSD), psilocybin, or other psychedelic drugs 2-4 times a week for at least several weeks, but potentially months or years. Concerningly, both LSD and psilocybin share structural similarities with medications which raise the risk of cardiac fibrosis and valvulopathy when taken regularly, including methysergide, pergolide, and fenfluramine. 3,4-Methylenedioxymethamphetamine, which is also reportedly used for microdosing, is likewise associated with heart valve damage when taken chronically. In this review, we evaluate the evidence that microdosing LSD, psilocybin, and other psychedelics for several months or more could raise the risk of cardiac fibrosis. We discuss the relationship between drug-induced cardiac fibrosis and the 5-HT2B receptor, and we make recommendations for evaluating the safety of microdosing psychedelics in future studies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video─potentially due to a "competition" between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Background: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males (n = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry., Results: Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups., Conclusions: Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups., Trial Registration:  ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ., (© 2024. The Author(s).)

Importance: Renewed interest in the clinical potential of hallucinogens may lead people with depression to a generally more positive view of the use of lysergic acid diethylamide (LSD). Therefore, past-year LSD use among people with depression may be increasing in prevalence., Objective: To assess time trends in the prevalence of past-year nonmedical LSD use by past-year major depression status and the variation in this association by sociodemographic characteristics., Design, Setting, and Participants: This survey study used pooled publicly available data from 478 492 adults aged 18 years or older who were administered the National Survey on Drug Use and Health from 2008 through 2019. Statistical analysis was conducted from December 2022 to June 2023., Main Outcome and Measures: Past-year major depression diagnoses per criteria from the DSM-IV were analyzed. Logistic regression models examined whether time trends in past-year nonmedical LSD use differed between adults with vs without past-year depression, adjusting for sociodemographic characteristics. Secondary analyses examined whether the trends in LSD use by depression status differed between sociodemographic subgroups., Results: The analytic sample included 478 492 adults, of whom 51.8% were female, 56.1% were younger than 50 years, 11.7% were Black, 15.1% were Hispanic, 65.8% were White, and 7.5% were another race. Weighted interview response rates ranged from 64.9% to 75.6% during the study time frame. From 2008 to 2019, past-year use of LSD increased significantly more among adults with major depression (2008 prevalence, 0.5%; 2019 prevalence, 1.8%; prevalence difference [PD], 1.3% [95% CI, 1.0%-1.6%]) compared with adults without major depression (2008 prevalence, 0.2%; 2019 prevalence, 0.8%; PD, 0.6% [95% CI, 0.5%-0.7%]) (difference in difference, 0.8% [95% CI, 0.5%-1.1%]). This difference was particularly pronounced among young adults aged 34 years or younger (PD among those aged 18-25 years with depression, 3.3% [95% CI, 2.5%-4.2%]; PD among those aged 26-34 years with depression, 2.7% [95% CI, 1.6%-3.8%]) and individuals with incomes less than $75 000 per year (PD among those with income <$20 000, 1.9% [95% CI, 1.3%-2.6%]; PD among those with income $20 000-$49 999, 1.5% [95% CI, 1.0%-2.1%]; PD among those with income $50 000-$74 999, 1.3% [95% CI, 0.7%-2.0%])., Conclusions and Relevance: This study suggests that, from 2008 to 2019, there was a disproportionate increase in the prevalence of past-year LSD use among US adults with past-year depression. Among those with depression, this increase was particularly strong among younger adults and those with lower household incomes. Among individuals with depression who also report LSD use, clinicians should discuss potential strategies for mitigating harm and maximizing benefits in medically unsupervised settings.

Background: Although studies have demonstrated that the use of lysergic acid diethylamide (LSD) is on the rise in the United States, it remains unclear how this trend looks across the hierarchical ladder of the American workforce. This is relevant given that LSD is increasingly being touted as a means of boosting creativity and performance, with mounting anecdotal evidence that business managers in particular are turning to it for inspiration and insight., Methods: Using pooled cross-sectional data from the National Survey on Drug Use and Health (2006-2014) on 168,920 adults in the United States employed full-time (weighted = 117,270,940), this study investigates how temporal trends in past year LSD use differ among business managers and non-managers., Results: The results suggest that the prevalence of past year LSD use increased over time at a greater rate among business managers than non-managers and that this difference cannot be accounted for by changes in business managers' perceived risk of LSD use or general substance use relative to non-managers., Conclusions: The study's findings indicate that temporal trends in past year LSD use depend on employees' hierarchical rank in their organization and suggest that business managers, regardless of gender, are becomingly increasingly interested in the potential competitive advantages that LSD may offer.

Background: Research with the Psychedelic Experience Questionnaire/Scale (PES) focuses on questions relating to mystical experience (Mystical Experience Questionnaire (MEQ)). The psychometric potential of the non-MEQ items of the PES remains largely unexplored., Aims: We investigated whether the PES also yields subscales besides the MEQ30 subscales., Methods: Data from 239 PES measurements (140 healthy participants) from six studies with moderate to high doses of lysergic acid diethylamide and/or psilocybin were included. New subscales (with items other than MEQ30) were created and validated as follows: (1) theoretical derivation of candidate items; (2) removal of items with rare experiences; (3) exploratory factor analysis; and (4) confirmatory factor analysis. Correlations of subscales within the PES and between the PES and the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) were performed. In addition, a cluster analysis using all items (except rare experiences) was performed., Results: The reliability of the four original factors of the MEQ30 was confirmed and four additional factors for the non-MEQ items were revealed: paradoxicality, connectedness, visual experience, and distressing experience. The first two additional factors were strongly correlated with the MEQ30 mystical subscale. Adding the new subscales to the MEQ30 subscales increased the explained variance with the 5D-ASC. The cluster analysis confirmed our main results and provided additional insights for future psychedelic psychometrics., Conclusion: The study yields a new validated 6-factor structure for extended mystical experience (MEQ40: MEQ30 + Paradoxicality + Connectedness) and covers psychedelic experience as a whole more comprehensively than has hitherto been possible within a single questionnaire (PES48). The entire PES (PES100) can also be used for further future psychedelic-psychometric research., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M. E. Liechti is a consultant for Mind Medicine Inc.

Psychedelics are classical hallucinogen drugs that induce a marked altered state of consciousness. In recent years, there has been renewed attention to the possible use of classical psychedelics for the treatment of certain mental health disorders. However, further investigation to better understand their biological effects in humans, their mechanism of action, and their metabolism in humans is needed when considering the development of future novel therapeutic approaches. Both metabolic and metabolomics studies may help for these purposes. On one hand, metabolic studies aim to determine the main metabolites of the drug. On the other hand, the application of metabolomics in human psychedelics studies can help to further understand the biological processes underlying the psychedelic state and the mechanisms of action underlying their therapeutic potential. This review presents the state of the art of metabolic and metabolomic studies after lysergic acid diethylamide (LSD), mescaline, N,N-dimethyltryptamine (DMT) and β-carboline alkaloids (ayahuasca brew), 5-methoxy-DMT and psilocybin administrations in humans. We first describe the characteristics of the published research. Afterward, we reviewed the main results obtained by both metabolic and metabolomics (if available) studies in classical psychedelics and we found out that metabolic and metabolomics studies in psychedelics progress at two different speeds. Thus, whereas the main metabolites for classical psychedelics have been robustly established, the main metabolic alterations induced by psychedelics need to be explored. The integration of metabolomics and pharmacokinetics for investigating the molecular interaction between psychedelics and multiple targets may open new avenues in understanding the therapeutic role of psychedelics., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Aims: Given the shifting landscape of hallucinogen use, particularly with increased therapeutic use, understanding current changes in use is a necessary part of examining the potential risk hallucinogens pose to vulnerable populations, such as young adults. This study aimed to measure hallucinogen use among young adults aged 19-30 years from 2018 to 2021., Design, Setting and Participants: This was a longitudinal cohort study among young adults aged 19-30 years from the US general population, interviewed between 2018 and 2021. Participants comprised 11 304 unique respondents, with an average number of follow-ups of 1.46 (standard deviation = 0.50). Of the observed data points, 51.9% were among females., Measurements: We examined past 12-month self-reported use of lysergic acid diethylamide (LSD), as well as hallucinogens besides LSD (e.g. psilocybin), monitoring any use as well as frequency, overall and by sex., Findings: From 2018 to 2021, past 12-month use of LSD among young adults in the US remained relatively unchanged, from 3.7% [95% confidence interval (CI) = 3.1-4.3] in 2018 to 4.2% in 2021 (95% CI = 3.4-5.0). Non-LSD hallucinogen [e.g. 'shrooms', psilocybin or PCP (phenylcyclohexyl piperidine)] use, however, increased in prevalence from 3.4% (95% CI = 2.8-4.1) to 6.6% from 2018 to 2021 (95% CI = 5.5-7.6). Across years, the odds of non-LSD use were higher for males [odds ratio (OR) = 1.86, 95% CI = 1.52-2.26] and lower for black than white participants (OR = 0.29, 95% CI = 0.19-0.47) and those without a college-educated parent (OR = 0.80, 95% CI = 0.64-0.99). Demographic disparities were similar for LSD use., Conclusion: Prevalence of past-year use non-lysergic acid diethylamide (LSD) hallucinogen was twice as high in 2021 as in 2018 among US young adults. Correlates of non-LSD hallucinogen use included being male, white and from higher socio-economic status backgrounds., (© 2023 Society for the Study of Addiction.)

Cultural awareness of anosmia and microsmia has recently increased due to their association with COVID-19, though treatment for these conditions is limited. A growing body of online media claims that individuals have noticed improvement in anosmia and microsmia following classic psychedelic use. We report what we believe to be the first three cases recorded in the academic literature of improvement in olfactory impairment after psychedelic use. In the first case, a man who developed microsmia after a respiratory infection experienced improvement in smell after the use of 6 g of psilocybin containing mushrooms. In the second case, a woman with anosmia since childhood reported olfactory improvement after ingestion of 100 µg of lysergic acid diethylamide (LSD). In the third case, a woman with COVID-19-related anosmia reported olfactory improvement after microdosing 0.1 g of psilocybin mushrooms three times. Following a discussion of these cases, we explore potential mechanisms for psychedelic-facilitated improvement in olfactory impairment, including serotonergic effects, increased neuroplasticity, and anti-inflammatory effects. Given the need for novel treatments for olfactory dysfunction, increasing reports describing improvement in these conditions following psychedelic use and potential biological plausibility, we believe that the possible therapeutic benefits of psychedelics for these conditions deserve further investigation.

Renewed interest in psychedelic substances in the 21 st century has seen the exploration of psychedelic treatments for various psychiatric disorders including substance use disorder (SUD). This review aimed to assess the effectiveness of psychedelic treatments for people with SUD and those falling below diagnostic thresholds (i.e. substance misuse). We systematically searched 11 databases, trial registries, and psychedelic organization websites for empirical studies examining adults undergoing psychedelic treatment for SUD or substance misuse, published in the English language, between 2000 and 2021. Seven studies investigating treatment using psilocybin, ibogaine, and ayahuasca, alone or adjunct with psychotherapy reported across 10 papers were included. Measures of abstinence, substance use, psychological and psychosocial outcomes, craving, and withdrawal reported positive results, however, this data was scarce among studies examining a wide range of addictions including opioid, nicotine, alcohol, cocaine and unspecified substance. The qualitative synthesis from three studies described subjective experience of psychedelic-assisted treatments enhanced self-awareness, insight, and confidence. At present, there is no sufficient research evidence to suggest effectiveness of any of the psychedelics on any specific substance use disorder or substance misuse. Further research using rigorous effectiveness evaluation methods with larger sample sizes and longer-term follow-up is required.

Psychedelic compounds have gained renewed interest for their potential therapeutic applications, but their metabolism and effects on complex biological systems remain poorly understood. Here, we present a systematic characterization of Lysergic Acid Diethylamide (LSD) metabolites in the model organism Caenorhabditis elegans using state-of-the-art analytical techniques. By employing ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry, we putatively identified a range of LSD metabolites, shedding light on their metabolic pathways and offering insights into their pharmacokinetics. Our study demonstrates the suitability of Caenorhabditis elegans as a valuable model system for investigating the metabolism of psychedelic compounds and provides a foundation for further research on the therapeutic potential of LSD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity., Methods: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 μg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here., Results: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points., Conclusions: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: People with terminal illnesses often experience psychological distress and associated disability. Recent clinical trial evidence has stimulated interest in the therapeutic use of psychedelics at end of life. Much uncertainty remains, however, mainly due to methodological difficulties that beset existing trials. We conducted a scoping review of pipeline clinical trials of psychedelic treatment for depression, anxiety, and existential distress at end of life., Methods: Proposed, registered, and ongoing trials were identified from 2 electronic databases (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform). Recent reviews and both commercial and non-profit organization websites were used to identify additional unregistered trials., Results: In total, 25 studies were eligible, including 13 randomized controlled trials and 12 open-label trials. Three trials made attempts beyond randomization to assess expectancy and blinding effectiveness. Investigational drugs included ketamine ( n  = 11), psilocybin ( n  = 10), 3,4-methylenedioxymethamphetamine ( n  = 2), and lysergic acid diethylamide ( n  = 2). Three trials involved microdosing, and fifteen trials incorporated psychotherapy., Significance of Results: A variety of onging or upcoming clinical trials are expected to usefully extend evidence regarding psychedelic-assisted group therapy and microdosing in the end-of-life setting. Still needed are head-to-head comparisons of different psychedelics to identify those best suited to specific indications and clinical populations. More extensive and rigorous studies are also necessary to better control expectancy, confirm therapeutic findings and establish safety data to guide the clinical application of these novel therapies.

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.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Background and Purpose: Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown., Experimental Approach: Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing., Key Results: LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D 2 (PGD 2 ) and F2α (PGF 2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9., Conclusions and Implications: The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome., (© 2022 British Pharmacological Society.)

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Psychedelics were used in the treatment of psychiatric conditions prior to their prohibition in the late 1960s. In the past three decades, there is a revived research interest in the therapeutic potential of psychedelic drugs with expected FDA approvals for treatment of various conditions. Given the exponential scientific growth of this field, we sought to characterize, analyze, and visualize trends in its top-cited articles. Bibliometric analyses are quantitative approaches to characterize a scientific field, including evaluation of the impact of academic literature. The bibliometric analysis and visualizations were conducted with R-tools for comprehensive science mapping. The top-cited 100 articles were cited between 82 and 668 times (median 125; mean 158). Fifty-four percent of the T100 articles were produced in the past decade (2010-2020). Network and author impact analysis highlighted key figures and primary collaboration networks within the top 100 publications. UK, USA, Switzerland, Spain, and Brazil lead the field. Results are discussed in terms of research growth, access, diversity, and the distribution of knowledge and experience in the field. These aggregated data and insights on the second wave of psychedelic research facilitate research evaluation, data-driven funding policies, and a practical map for researchers and clinicians entering the field.

Fibromyalgia (FM) is a difficult to treat chronic pain condition for which there is strong interest in alternative treatments. There is growing interest in the potential of psychedelic substances (e.g., psilocybin) in conjunction with psychotherapy to treat chronic pain. Via a cross-sectional, anonymous, online survey, we aimed to characterize knowledge, perceptions, and past use of serotonergic ("classic") and non-serotonergic psychedelics among a population of individuals with FM, and to investigate interest in psychedelic-based FM treatments. Among a North American population of 354 participants with FM, 29.9% reported past use of a psychedelic, with lysergic acid diethylamide (LSD) and psilocybin mushrooms being most commonly used. Perceptions of benefit from psychedelic use were generally neutral (59.4%) or positive (36.8%), with <3% reporting negative impacts on overall health or pain symptoms. Among 12 participants who used psychedelics with intentions of treating chronic pain, 11 reported improved symptoms. Regardless of past use, the majority of participants believed that psychedelics have potential for chronic pain treatments and would be willing to participate in a psychedelic-based clinical trial for their pain. These findings support the need for additional studies to understand the potential and effectiveness of psychedelic substances in managing FM symptoms.

Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT 2A ) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT 2A receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use., (Copyright: © 2023 Permanyer.)

There has been a reemergence of research into the use of substances such as LSD, MDMA, and psilocybin for the treatment of psychiatric disorders. This increase in consideration toward the medicinal use of these compounds has been termed the "Psychedelic Renaissance." This article specifically explores the background of psilocybin, a psychoactive compound that is naturally derived from certain species of fungi. Pubmed was searched by one doctoral-level researcher using specific Boolean operator terms. The results were filtered by title and abstract and 76 articles were screened and analyzed in full detail. Oral psilocybin is showing itself to be clinically efficacious by producing statistically significant reductions in depression and anxiety symptoms over time versus control in multiple clinical trials. It has also been shown to reduce cigarettes per day and drinks per day in patients with substance use disorders. Thus far, there have been no significant adverse clinical events from psilocybin and there also have been no verifiable recorded deaths reported. Larger studies need to be performed before the drug can potentially become approved for use in the general population.

Objective: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder., Methods: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria., Results: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient., Conclusions: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Hallucinations are one of the most interesting and least understood of all human experiences. This commentary addresses the ideas which most influenced my thinking in the past 20 years and what I believe to be the most currently promising area of enquiry. Interest in hallucinations reaches far back into antiquity and across cultures. The similarity of hallucinations in mental illness with the perceptual experiences reported by individuals who not mentally unwell has long been recognized. Early scientific research on hallucinogen drugs such as lysergic acid diethylamide (LSD) was criticized and then withdrawn, but its recent revival offers new opportunities to examine the mechanism and 'process' of hallucinating. Many psychedelic compounds can elicit intense and realistic hallucinations. The study of hallucinogens conducted in carefully controlled and supervised settings and with individuals who are not mentally unwell opens exciting new possibilities. For example, it may be possible to study the temporal shifts in perceptual awareness, decode what influences the contents, affect, meaning, and appraisals of hallucinations and guide novel psychotherapy techniques and drug therapy., Competing Interests: Declaration of Competing Interest Nil., (Copyright © 2022. Published by Elsevier B.V.)

Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors (STBs). MDMA/ecstasy and classic psychedelics represent two areas for exploration, as use of these substances has been associated with both increased and lowered odds of STBs. Thus, the goal of this study was to test the associations between MDMA/ecstasy and classic psychedelics (psilocybin, peyote, mescaline, LSD) and STBs in a nationally representative sample of U.S. adolescents. We tested these associations in a sample of adolescents aged 12-17 years old from the National Survey on Drug Use and Health (2004-2019) (N = 262,617) using survey-weighted multivariable logistic regression models. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (aOR range 0.77-0.85). Conversely, LSD was associated with increased odds of these same outcomes (aOR range 1.20-1.35). MDMA/ecstasy, peyote, and mescaline did not share associations with STBs. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth., (© 2022. The Author(s).)

Rationale: The use of psychedelics for medical and recreational purposes is rising. Contextual factors such as expectancy, intention, and sensory and social environment (set and setting) are widely recognized as moderating the effects of these substances. Nevertheless, clinical trials of microdosing - the ingestion of small, sub-hallucinogenic doses of psychedelics - rarely report their set and setting. This fact suggests that such factors are not considered important in the context of microdosing., Objective: This paper challenges this assumption and makes the case for the crucial relevance of set and setting in microdosing practice. Building on set and setting theory and placebo theory, we explain why set and setting are of crucial importance in the case of microdosing., Results: This reasoning helps elucidate the role of set and setting in determining the outcomes of microdosing and helps explain some of the contradictory results that have emerged in microdosing research in recent years., Conclusion: Set and setting are important constructs to be considered especially in the context of microdosing psychedelics. By reporting set and setting, the results of microdosing research can be made more reliable and consistent., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: Hallucinogen use is potentially harmful. Information on whether such use has increased in recent decades is lacking. This study assessed overall and age-specific time trends in the prevalence of 12-month hallucinogen use in the US general population., Design: Cross-sectional., Setting: Data from the US National Survey on Drug Use and Health, 2002-19., Participants: Respondents aged ≥ 12 years (n = 1 006 051)., Measurements: Predictors were continuous years. Outcome variables included any hallucinogen use and use of lysergic acid diethylamide (LSD), ecstasy and phencyclidine (PCP) in the past year. Socio-demographic variables (gender, age, race/ethnicity, educational level and family income) were covariates., Findings: Overall, hallucinogen use increased between 2015 and 2019 [prevalence difference (PD) = +0.44, P < 0.05]. Since 2002, hallucinogen use has increased in adults aged ≥ 26 years (PD, 2002-14 = +0.24, P < 0.05; PD, 2015-19 = +0.45, P < 0.001) and decreased in adolescents aged 12-17 years (PD, 2002-14 = -1.60, P < 0.0001; PD, 2015-19 = -0.73, P < 0.001). Ecstasy use has decreased in adolescents (PD, 2002-14 = -0.56, P < 0.001), adults aged 18-25 years (PD, 2015-19 = -0.96, P < 0.01) and ≥ 26 years (PD, 2015-19 = -0.13, P < 0.05). LSD use between 2002 and 2019 increased overall (PD = +0.71, P < 0.0001) and in all age groups (12-17: PD = +0.67, P < 0.001; 18-25: PD = +3.12, P < 0.0001; ≥ 26: PD = +0.36, P < 0.0001). Conversely, PCP use between 2002 and 2019 decreased overall (PD = -0.06, P < 0.001), in adolescents (PD = -0.24, P < 0.001) and young adults (PD = -0.32, P < 0.0001)., Conclusions: Since 2002, hallucinogen use in the United States has decreased among adolescents but increased in adults and is now estimated to affect more than 3 million adults aged 26+ years and more than 5.5 million adults aged 18+ years., (© 2022 Society for the Study of Addiction.)

Competing Interests: Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no interests to declare.

Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT 2A R) agonist psychedelic compounds has increased dramatically over the past two decades. In humans, these compounds produce drastic effects on consciousness, and their therapeutic potential relates to changes in the processing of emotional, social, and self-referential information. The use of animal behavior to study psychedelics is under debate, and this review provides a critical perspective on the translational value of animal behavior studies in psychedelic research. Acute activation of 5-HT 2A Rs produces head twitches and unique discriminative cues, disrupts sensorimotor gating, and stimulates motor activity while inhibiting exploration in rodents. The acute treatment with psychedelics shows discrepant results in conventional rodent tests of depression-like behaviors but generally induces anxiolytic-like effects and inhibits repetitive behavior in rodents. Psychedelics impair waiting impulsivity but show discrepant effects in other tests of cognitive function. Tests of social interaction also show conflicting results. Effects on measures of time perception depend on the experimental schedule. Lasting or delayed effects of psychedelics in rodent tests related to different behavioral domains appear to be rather sensitive to changes in experimental protocols. Studying the effects of psychedelics on animal behaviors of relevance to effects on psychiatric symptoms in humans, assessing lasting effects, publishing negative findings, and relating behaviors in rodents and humans to other more translatable readouts, such as neuroplastic changes, will improve the translational value of animal behavioral studies in psychedelic research. SIGNIFICANCE STATEMENT: Psychedelics like LSD and psilocybin have received immense interest as potential new treatments of psychiatric disorders. Psychedelics change high-order consciousness in humans, and there is debate about the use of animal behavior studies to investigate these compounds. This review provides an overview of the behavioral effects of 5-HT 2A R agonist psychedelics in laboratory animals and discusses the translatability of the effects in animals to effects in humans. Possible ways to improve the utility of animal behavior in psychedelic research are discussed., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions., Objective: To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies., Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies., Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies., Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

To date, the clinical and scientific literature has best documented the effects of classical psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), in typical quantities most often associated with macrodosing. More recently, however, microdosing with psychedelics has emerged as a social trend and nascent therapeutic intervention. This variation in psychedelic practice refers to repeat, intermittent ingestion of less-than-macrodose amounts that do not cause the effects associated with full-blown "trips". Microdosing paves the road to incorporating psychedelic drugs into a daily routine while maintaining, or even improving, cognitive and mental function. Unlike macrodosing with psychedelics, the influence of microdosing remains mostly unexplored. And yet, despite the paucity of formal studies, many informal accounts propose that microdosing plays an important role as both a therapeutic intervention (e.g., in mental disorders) and enhancement tool (e.g., recreationally-to boost creativity, improve cognition, and drive personal growth). In response to this relatively new practice, we provide an integrative synthesis of the clinical, social, and cultural dimensions of microdosing. We describe some of the overarching context that explains why this practice is increasingly in vogue, unpack potential benefits and risks, and comment on sociocultural implications. In addition, this article considers the effects that macro- and microdoses have on behavior and psychopathology in light of their dosage characteristics and contexts of use.

Microdosing-the intermittent ingestion of minute, sub-hallucinogenic amounts of psychedelic substances, repeatedly and over time-has become a widespread, albeit largely understudied, phenomenon. Regulations around using psychedelics at any dose-micro, mini, macro, or mega-pose all sorts of difficulties for those who wish to systematically study the effects of Schedule I drugs, especially in the United States. Microdosers commonly claim that taking a sub-hallucinogenic (pre-hallucinogenic or sub-perceptual) dose improves higher brain functions, including creativity, productivity, and mood. If true, these results would provide an important experimental edge in distinguishing psychosocial effects (e.g. caused by expectation) from those related to the active psychedelic ingredient. In this critical integrative synthesis, we explore the psychobiological science of dose amounts and how it informs microdosing with classical psychedelics (e.g. lysergic acid diethylamide [LSD] and psilocybin) to highlight and fuel research into questions (e.g. in cognitive neuroscience, consciousness studies, and metacognition). We sketch the hurdle-laden regulatory landscape and the procedures that shroud research with Schedule I drugs. Finally, we offer some future directions relevant to both scholars and clinicians in the social and behavioral sciences as well as in mental health and neurological science.

Objectives: Different psychoactive substances are widely used in today's society. So far limited data are available on the use of psychedelics in the general population. The main aim of this study is to estimate the numbers of users of substances with psychedelic properties (classical psychedelics, cannabis, ecstasy, and ketamine) in the Czech Republic., Methods: Data from two samples enrolled in representative cross-sectional questionnaire surveys in the Czech adult population in 2016 (n = 2,785) and 2018 (n = 1,665) were analysed. Prevalence rates were extrapolated to estimate numbers of current, i.e., last-year, users of psychedelics, and their socio-demographic profiles were compared with non-users and users of cannabis., Results: An estimated 5-6% of the Czech adult population (350-430 thousand people) used classical psychedelics (LSD, psilocybin mushrooms, ayahuasca) in their lifetime, increasing up to 28-30% when cannabis is included (1.9-2.1 million users). Current use of classical psychedelics reached 0.7-1.9% (50-130 thousand people), and 9-11% (590-750 thousand users) when cannabis was included. Users of psychedelics were more often males, of younger age and single., Conclusions: No significant socio-demographic differences were found between users of classical psychedelics and recreational cannabis users, however, differences were significant when compared to non-users and users of other illicit drugs. Findings should further serve to inform drug policy and social and healthcare systems in respect to the use of psychedelics.

Background: There is renewed interest in the clinical application of hallucinogenic substances to treat a range of psychiatric conditions. However, there is mixed evidence regarding how use of such substances outside of medical settings relates to psychological distress, depression, and suicidality., Methods: We examined data from a US representative sample of noninstitutionalized adults from the 2015-2020 National Survey on Drug Use and Health (N = 241,675). We evaluated whether past-year use of specific hallucinogens (i.e., LSD, DMT/AMT/Foxy, salvia divinorum, ecstasy [MDMA/Molly], ketamine) is associated with reporting past-year serious psychological distress (SPD), major depressive episode (MDE), and suicidality. Generalized linear models using Poisson and log link were used to estimate adjusted prevalence ratios (aPRs), controlling for sociodemographic characteristics and past-year use of various other illegal drugs., Results: LSD use was associated with an increased likelihood of MDE (aPR = 1.23, 95% CI: 1.10-1.37) and suicidal thinking (aPR = 1.21, 95% CI: 1.09-1.34). Similar associations were observed between salvia divinorum use and suicidal thinking (aPR = 1.41, 95% CI: 1.00-1.97) and between DMT/AMT/Foxy use and suicidal planning (aPR = 1.81 95% CI: 1.17-2.81). On the other hand, ecstasy use was associated with a decreased likelihood of SPD (aPR = 0.83, 95% CI: 0.77-0.89), MDE (aPR = 0.91, 95% CI: 0.83-1.00), and suicidal thinking (aPR = 0.86, 95% CI: 0.75-0.99)., Conclusion: Findings suggest there are differences among specific hallucinogens with respect to depression and suicidality. More research is warranted to understand consequences of and risk factors for hallucinogen use outside of medical settings among adults experiencing depression or suicidality., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Both psychedelic drug experiences and near-death experiences can occasion changes in perspectives on death and dying, but there have been few direct comparisons of these phenomena. This study directly compared psychedelic occasioned and non-drug experiences which altered individuals' beliefs about death. Individuals who reported an experience that altered their beliefs about death occasioned by either a psychedelic drug or a near-death or other non-ordinary experience completed an online survey. Circumstances of the experience, mystical and near-death subjective features, changes in attitudes about death, and other persisting effects were evaluated. The study sample (n = 3192) included five groups: non-drug near-death or other non-ordinary experiences (n = 933), and drug experiences occasioned by lysergic acid diethylamide (LSD) (n = 904), psilocybin (n = 766), ayahuasca (n = 282), or N,N-dimethyltryptamine (DMT) (n = 307). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. Compared to the psychedelic groups, the non-drug group was more likely to report being unconscious, clinically dead, and that their life was in imminent danger. The groups were remarkably similar in the reported changes in death attitudes attributed to the experience, including a reduced fear of death and high ratings of positive persisting effects and personal meaning, spiritual significance, and psychological insight. Although both psychedelic and non-drug participants showed robust increases on standardized measures of mystical and near-death experiences, these measures were significantly greater in the psychedelic participants. Non-drug participants were more likely to rate their experiences as the single most meaningful of their lives. Comparing across psychedelic substances, ayahuasca and DMT groups tended report stronger and more positive enduring consequences of the experience than the psilocybin and LSD groups, which were largely indistinguishable. These data provide a detailed characterization and comparison of psychedelic occasioned and non-drug experiences that changed attitudes about death and suggest the importance of future prospective psychedelic administration studies., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RRG and TCS are members of the Board of Directors of the Heffter Research Institute. TCS is director of the RiverStyx Foundation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT 2A R) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT 2A R antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT 2A R agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT 2A R density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT 2A R, is not observable upon repeated administration of nonpsychedelic 5-HT 2A R agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

Introduction: 25B-NBOH is a synthetic hallucinogen closely related to the "NBOMe" family of N-substituted 2C phenethylamine derivatives. There have been no published reports documenting the clinical toxicity of NBOH derivatives., Case Series: Five patients presented to the Emergency Department (ED) with altered conscious state following exposure to powder sold as "powdered LSD" at a party. A 24-year-old male who ingested the powder developed mydriasis, tachycardia, hypertension, and severe agitation requiring parenteral sedation. A 22-year-old male who insufflated the powder developed status epilepticus requiring intubation. Both patients developed acute kidney injury and one had rhabdomyolysis. In both cases, blood analysis detected 25-NBOH and no other illicit/licit drugs. Three other patients developed mild hallucinations. Hyperthermia was not documented in any case., Discussion: Exposure to 25B-NBOH in a powdered form produced sympathomimetic toxicity, including hallucinations. Insufflation of 25B-NBOH led to rapid onset of status epilepticus in one case. Toxicity in all cases resolved within 12 h. Despite in vitro evidence of 5-HT 2A receptor agonism, hyperthermia was not observed. Potent hallucinogens are often delivered via blotter paper to avoid excessive dosing. The severe clinical toxicity documented in these cases highlights the potential for development of adverse health effects with exposure to apparent small volumes of potent sympathomimetics.

Background: Psychedelics, like lysergic acid diethylamide (LSD), are again being studied as potential therapies for many neuropsychiatric disorders, including addictions. At the same time, the acute effects of psychedelics on rewarding behaviours have been scarcely studied., Aims: The current study aimed to clarify if LSD decreases binge-like ethanol drinking in mice, and whether the observed acute effects on ethanol consumption are generalizable to a natural reinforcer, sucrose, and if the effects resulted from aversive or reward-attenuating effects caused by LSD., Methods: The effects of acute LSD were examined using 2-bottle choice intermittent ethanol (20%) and sucrose drinking (10%), discrete-trial current-intensity threshold method of intracranial self-stimulation and short-term feeding behaviour assay in C57BL/6 male mice., Results: The results showed that acute 0.1 mg/kg, but not 0.05 mg/kg, dose (i.p.) of LSD reduced 2-h intermittent ethanol drinking transiently without any prolonged effects. No effects were seen in intermittent 2-h sucrose drinking. The tested LSD doses had neither effect on the intracranial self-stimulation current-intensity thresholds, nor did LSD affect the threshold-lowering, or rewarding, effects of simultaneous amphetamine treatment. Furthermore, LSD had small, acute diminishing effects on 2-h food and water intake., Conclusions: Based on these results, LSD decreases binge-like ethanol drinking in mice, but only acutely. This effect is not likely to stem from reward-attenuating effects but could be in part due to reduced consummatory behaviour.