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Different study designs of psychedelic trials may impact the blinding and expectance, leading to biased treatment effects. This study aimed to examine the association between antidepressant efficacy and study designs in psychedelic trials. Six databases were systematically searched. Eligible trials were required to investigate the efficacy of psychedelics (psilocybin, lysergic acid diethylamide [LSD], 3,4-Methylenedioxymethamphetamine [MDMA], and ayahuasca) in adult patients with depressive symptoms. We only considered oral psychedelic-assisted therapy without concomitant use of antidepressants. The primary outcome was the change in depressive symptoms. There were five study designs of psychedelic trials, including non-active-drug-as-placebo, active-drug-as-placebo, waitlist-as-control, fixed-order, and pre-post designs. In non-active-drug -as-placebo design, psilocybin (k = 4, Hedges' g [g] = 0.87, 95 % confidence intervals[CIs] = 0.58 to 1.16) and MDMA (k = 2, g = 0.65, 95%CIs = 0.26 to 1.05) were associated with large and medium effect sizes, respectively. In active-drug-as-placebo design, both psilocybin (k = 2, g = 0.71, 95%CIs = −0.01 to 1.43) and MDMA (k = 3, g = 0.53, 95%CIs = −0.23 to 1.28) were not statistically significant. In pre-post single-arm (k = 3, g = 2.51, 95%CIs = 1.00 to 4.02) and waitlist-as-control (k = 1, g = 2.88, 95%CIs = 1.75 to 4.00) designs, psilocybin showed a large effect size of antidepressant effect. Ayahuasca also showed a large effect size in both pre-post (k = 2, g = 1.88, 95%CIs = 1.18 to 2.57) and non-active-drug-as-placebo (k = 1, g = 1.60, 95%CIs = 0.84 to 2.36) designs. LSD was associated with a significant antidepressant effect only in non-active-drug-as-placebo design (k = 1, g = 1.49, 95%CIs = 0.80 to 2.17) but not in active-drug-as-placebo design (k = 1, g = 0.44, 95%CIs = −0.90 to 1.78). The antidepressant effects of psychedelics may be overestimated in studies with pre-post single-arm, non-active-drugs-as placebo, and waitlist-control designs. Restricted sample size, difficulty with establishing blinding for participants, and over expectancy limit the estimation of the antidepressant effect of psychedelic-assisted therapy. • The antidepressant effects of psychedelics may be overestimated in studies with pre-post single-arm, non-active-drugs-as placebo, or waitlist-control designs. • In non-active-drug-as-placebo design, psilocybin, MDMA, and LSD were associated with better efficacy than placebo. • In active-drug-as-placebo design, psilocybin MDMA, and LSD were not significantly associated with better efficacy than placebo. • In meta-regression, we identified that the higher dose of psilocybin is associated with a better antidepressant effect. [ABSTRACT FROM AUTHOR]

Dans cet article, nous avons pour objectif de décrire un modèle interdisciplinaire de psychothérapie assistée par psychédéliques (PAP) que nous avons développé dans un cadre institutionnel aux hôpitaux universitaires de Genève. La psychothérapie assistée par psychédéliques (PAP) est une approche psychothérapeutique exploitant l'altération de l'état de conscience induite par une substance psychédélique. Cette approche, longtemps négligée pour des raisons historiques non scientifiques, fait de nouveau l'objet de recherches grâce à des résultats préliminaires importants concernant son potentiel thérapeutique dans divers troubles mentaux. En Suisse, depuis 2014, il est possible d'obtenir des autorisations médicales exceptionnelles pour traiter des patients avec du LSD et de la psilocybine. Nous soutenons que l'altération de la conscience induite par les psychédéliques est un outil thérapeutique puissant qui pourrait être développé pour appuyer la psychothérapie traditionnelle basée sur le dialogue afin de relancer le processus psychothérapeutique. In this article, we aim to describe an interdisciplinary model for psychedelic assisted psychotherapy (PAP) that we have developed at the Geneva University Hospitals, in an institutional setting. Our model integrates the collaborative efforts of psychiatrists, psychologists, and nurses establishing a structured framework for administering PAP in a safe, controlled, and standardized manner. Psychedelic assisted psychotherapy (PAP) is a psychotherapeutic approach that utilizes the profound alteration of the state of consciousness induced by psychedelic substances to enhance therapeutic outcomes. This innovative approach, which has been neglected due to historical biases rather than empirical evidence, is now experiencing a renewed interest among clinicians. Contemporary research, equipped with advanced methodologies and a rigorous scientific approach, is showing significant therapeutic potential for a range of mental health disorders. In Switzerland, the legal framework authorizes the medicinal use since 2014 for exceptional authorizations for the medicinal use of LSD and psilocybin for therapeutic purposes, under strict regulations. We provide a comprehensive description of the PAP protocol implemented at the Geneva University Hospitals, beginning with its inception in September 2020. Our methodological outline includes the administrative and clinical selection criteria for patient eligibility; the preparatory sessions designed to introduce the patients with psychoeducation interventions and the analysis of intention and therapeutical objectives; the controlled administration of psychedelics in a supportive environment; and the integration sessions that follow psychedelic experiences. Our protocol emphasizes safety, ethical considerations, and the importance of a supportive therapeutic relationship throughout the process. We also describe questionnaires we use to qualify and assess the alteration in the state of consciousness, namely The Five Dimension Altered States of Consciousness (5AD-ASC) and the Mystical Experience Questionnaire (MEQ). Since the start of the program in September 2020 and up to February 2024, a total of 224 personal authorizations (114 LSD, 110 Psilocybin) have been issued to the Geneva University Hospital PAP team, for a total of 396 individual sessions. The core argument presented in this article is that the psychedelic-induced alteration of consciousness is a novel therapeutic tool, which works as a potent catalyst that can be synergistically combined with traditional dialogue-based psychotherapy. This combination has the potential to support the psychotherapeutic processes and enable breakthroughs in cases where conventional therapy has reached its limits. We discuss the implications of this approach, reflecting on both its challenges and its transformative potential within its clinical application. The conclusion of our article is an endorsement of the continued basic and clinical research on PAP. By presenting a detailed framework of the PAP process, including its preparatory, experiential, and integrative phases, we advocate for a structured and scientifically grounded exploration of its therapeutic efficacy. Our conclusion calls for a broader acceptance and integration of PAP within clinical practice, provided it is underpinned by ongoing research, ethical practice, and institutional support. [ABSTRACT FROM AUTHOR]

Improving safe and effective access to ketamine therapy is of high priority given the growing burden of mental illness. Telehealth-supported administration of sublingual ketamine is being explored toward this goal. In this longitudinal study, moderately-to-severely depressed patients received four doses of ketamine at home over four weeks within a supportive digital health context. Treatment was structured to resemble methods of therapeutic psychedelic trials. Patients receiving a second course of treatment were also examined. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression. We conducted preregistered machine learning and symptom network analyses to investigate outcomes (osf.io/v2rpx). A sample of 11,441 patients was analyzed, demonstrating a modal antidepressant response from both non-severe (n = 6384, 55.8 %) and severe (n = 2070, 18.1 %) baseline depression levels. Adverse events were detected in 3.0–4.8 % of participants and predominantly neurologic or psychiatric in nature. A second course of treatment helped extend improvements in patients who responded favorably to initial treatment. Improvement was most strongly predicted by lower depression scores and age at baseline. Symptoms of Depressed mood and Anhedonia sustained depression despite ongoing treatment. This study was limited by the absence of comparison or control groups and lack of a fixed-dose procedure for ketamine administration. At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement in patients with depression. Strategies for combining psychedelic-oriented therapies with rigorous telehealth models, as explored here, may uniquely address barriers to mental health treatment. • Telehealth ketamine assisted treatment was safe and effective for 11,000+ patients. • Machine learning identified patient characteristics predicting symptoms improvement. • Temporal network suggested low mood and anhedonia as key in treatment non-response. • Primarily psychiatric adverse events underscored importance of behavioral support. • Telehealth-supported ketamine administration may help address barriers to treatment. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Perturbations of consciousness arise from the interplay of brain network architecture, dynamics, and neuromodulation , providing the opportunity to interrogate the effects of these elements on behaviour and cognition. Fundamental building blocks of brain function can be identified through the lenses of space, time, and information. Each lens reveals similarities and differences across pathological and pharmacological perturbations of consciousness, in humans and across different species. Anaesthesia and brain injury can induce unconsciousness via different mechanisms, but exhibit shared neural signatures across space, time, and information. During loss of consciousness, the brain's ability to explore functional patterns beyond the dictates of anatomy may become constrained. The effects of psychedelics may involve decoupling of brain structure and function across spatial and temporal scales. Disentangling how cognitive functions emerge from the interplay of brain dynamics and network architecture is among the major challenges that neuroscientists face. Pharmacological and pathological perturbations of consciousness provide a lens to investigate these complex challenges. Here, we review how recent advances about consciousness and the brain's functional organisation have been driven by a common denominator: decomposing brain function into fundamental constituents of time, space, and information. Whereas unconsciousness increases structure–function coupling across scales, psychedelics may decouple brain function from structure. Convergent effects also emerge: anaesthetics, psychedelics, and disorders of consciousness can exhibit similar reconfigurations of the brain's unimodal–transmodal functional axis. Decomposition approaches reveal the potential to translate discoveries across species, with computational modelling providing a path towards mechanistic integration. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

• Acute psilocybin induced Fos expression in a number of brain regions in male rats. • This Fos was expressed in both neurons and oligodendrocytes. • Psilocybin-induced Fos expression was especially robust in the central amygdala. • Initial activation of these brain areas may participate in psilocybin's long-lasting therapeutic effects. Psilocybin has received attention as a treatment for depression, stress disorders and drug and alcohol addiction. To help determine the mechanisms underlying its therapeutic effects, here we examined acute effects of a range of behaviourally relevant psilocybin doses (0.1–3 mg/kg SC) on regional expression of Fos, the protein product of the immediate early gene, c-fos in brain areas involved in stress, reward and motivation in male rats. We also determined the cellular phenotypes activated by psilocybin, in a co-labeling analysis with NeuN, a marker of mature neurons, or Olig1, a marker of oligodendrocytes. In adult male Sprague-Dawley rats, psilocybin increased Fos expression dose dependently in several brain regions, including the frontal cortex, nucleus accumbens, central and basolateral amygdala and locus coeruleus. These effects were most marked in the central amygdala. Double labeling experiments showed that Fos was expressed in both neurons and oligodendrocytes. These results extend previous research by determining Fos expression in multiple brain areas at a wider psilocybin dose range, and the cellular phenotypes expressing Fos. The data also highlight the amygdala, especially the central nucleus, a key brain region involved in emotional processing and learning and interconnected with other brain areas involved in stress, reward and addiction, as a potentially important locus for the therapeutic effects of psilocybin. Overall, the present findings suggest that the central amygdala may be an important site through which the initial brain activation induced by psilocybin is translated into neuroplastic changes, locally and in other regions that underlie its extended therapeutic effects. [ABSTRACT FROM AUTHOR]

Blinding of treatment allocation in clinical trials in psychiatry is regarded as an ideal. The potential impact of unblinding chimes with a general concern for psychological research: so-called demand characteristics can undermine confidence in findings from experimental and clinical studies. Scepticism can result in nihilism. The reliance on subjective report of symptoms in clinical trials of drug efficacy in depression provides an important example. It is regularly implied that if subjective effects, including specific adverse reactions, unblind participants to an active treatment then evidence for its efficacy is suspect. In fact, the strong association between dose and subjective effects does not translate into a strong relationship with efficacy in randomised controlled trials (RCTs) of conventional antidepressant drugs; this observation falsifies the proposition that unblinding is the principal mechanism driving RCT outcomes in studies of depression. Instead, changes in brain function, that occur soon after treatment starts, do predict treatment outcomes and align with our understanding of neurotransmitter effects from neuroscience. Psychedelic experience for the treatment of depression must be unblinding, but the effect results directly from serotonergic receptor activation and changes in brain connectivity. Where such effects are part of a novel mechanism of action, a strong dose response relationship would be expected, irrespective of unblinding. We highlight the importance of exploring blinding as a mechanism, confirming dose-related outcomes, and dissociating unblinding effects from efficacy. Unblinding does not necessarily invalidate the subjective experience of sustained recovery from depression. • Does unblinding in treatment of mood disorders merit nihilism or science? • Unblinding by adverse reactions does not explain conventional antidepressant efficacy • Dose and biomarkers of psilocybin effect correlate with subjective experience • Subjective psychedelic experiences are correlated with clinical outcome [ABSTRACT FROM AUTHOR]

COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD—the largest randomised controlled clinical trial of psilocybin—to discuss findings of the exploratory efficacy endpoints. In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients. [ABSTRACT FROM AUTHOR]

Ketamine is an NMDA receptor antagonist that has antidepressant and anesthetic properties. At subanesthetic doses, ketamine induces transient psychosis in humans, and is used to model psychosis in experimental animals. In rodents, subanesthetic doses of ketamine increase the power of high-frequency oscillations (HFO, > 100 Hz) in the electroencephalogram (EEG), a frequency band linked to cognitive functions. However, to date, the effects of ketamine in carnivores and primates have been poorly investigated. Here, we examined in the cat, cortical HFO during wakefulness, sleep, and after administering a sub-anesthetic dose of ketamine. Four cats were prepared with cortical electrodes for chronic polysomnographic recordings in head-restrained conditions. The cortical HFO power, connectivity, direction of the information flow using Granger Causality (GC) analysis, their relationships with respiratory activity, and the effect of auditory stimulation were analyzed. During wakefulness, but not during sleep, we found that HFO were coupled with the inspiratory phase of the respiration. After ketamine administration, HFO power was enhanced and remained associated with the inspiratory phase. GC analysis suggests that ketamine-enhanced HFO originate from the olfactory bulb (OB) and stream towards the prefrontal cortex (Pf). Accordingly, occluding the nostrils significantly reduced the power of the ketamine-enhanced HFO in both the OB and Pf. Finally, auditory stimulation did not affect HFO. In conclusion, the HFO are associated with respiration during wakefulness, but not during sleep. The enhancement of this rhythm by ketamine may disrupt cortical information processing, which could contribute to some of the neuropsychiatric effects associated with ketamine. [Display omitted] • High-frequency oscillations (HFO) are modulated by respiration during wakefulness. • Subanesthetic doses of ketamine increase the power of HFO. • Under ketamine, HFO are coupled with the inspiratory phase of respiration. • Ketamine-induced HFO originate in the olfactory bulb and stream to the neocortex. • HFO were not affected by auditory stimulation. [ABSTRACT FROM AUTHOR]

(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies. [ABSTRACT FROM AUTHOR]

Treating amotivated states remains difficult. Classical psychedelic drugs (5-HT 2A receptor agonists) such as LSD and psilocybin have shown therapeutic potential in treating such symptoms, but their development has been hindered by their undesirable hallucinogenic effects. There is increasing evidence that administration of psychedelics at dose levels too low to evoke a hallucinogenic effect ("microdoses") may have therapeutic value in contexts of mood and cognition. 2,5-Dimethoxy-4-propylamphetamine (DOPR) is a psychedelic phenethylamine compound acting as a 5-HT 2A receptor agonist. We used a combination of behavioral assays to determine the motivational and hallucinogenic-like effects of DOPR and identify the dose ranges at which each of these effects were observed. In mice, the motivational effects of psychedelic compounds were assessed using the progressive ratio breakpoint task (PRBT, n = 80), a translational assay sensitive to changes in motivation. Psychedelic-like effects were gauged using the mouse head-twitch response (HTR, n = 72) assay, a preclinical readout of psychedelic potential. Significant improvements in PRBT performance were seen at doses as low as 0.0106 mg/kg in animals with low baseline PRBT scores while high-performing PRBT mice were unaffected. DOPR only induced significant HTR at doses ≥0.1 mg/kg. Together, these results indicate that the psychedelic DOPR may increase motivation in those with a low motivated state. Importantly, these effects may be attainable at low doses below the threshold required to induce psychedelic subjective effects. Hence, the ability of low doses of DOPR and other psychedelic drugs to alleviate amotivated states in rodents manipulated to induce disease-relevant states should be investigated. • Low doses of psychedelics may treat amotivated states in disorders like MDD. • DOPR is an established psychedelic compound acting as a 5-HT2A receptor agonist. • DOPR treatment increased progressive ratio breakpoint (motivation) in mice. • DOPR-induced increase in motivation was at doses too low to evoke psychedelic effects. • Microdoses of DOPR may treat amotivation without unwanted side-effects. [ABSTRACT FROM AUTHOR]

Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT 2A receptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving male mice after administration of the 5-HT 2A/2C receptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results suggest that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties. • DOI disrupts the typical increase in 1–4 Hz delta power that occurs when mice are at rest. • DOI increases 50–90 Hz gamma power irrespective of behavioral state. • DOI decreases the firing rate of fast-spiking neurons irrespective of behavioral state. • DOI increases the proportion of low-spiking neurons which increase their firing rate when mice are active. [ABSTRACT FROM AUTHOR]

There is renewed research attention on the use of psychedelic drugs to treat psychiatric illnesses. If psychedelic drugs are approved for medical use in the United States, patients, professionals, and policy makers will look to pharmacists as medication experts for advice on the safe, effective, and ethical use of these substances. To help prepare a future generation of pharmacists in this therapeutic area, a psychedelic psychopharmacology elective was developed and piloted. Broadly, the objectives of the course were to train students to (1) analyze scientific literature, (2) engage in ethical discussions, and (3) make evidence-based clinical recommendations about the use of psychedelics. The pilot elective course was delivered synchronously online to 12 second- and third-year pharmacy students during spring 2021. Activities included journal clubs, textbook reading assignments, reflective structured dialogues, a monograph, and a term paper. The course was feasible for a single instructor and well-received by students. A mix of instructor-directed and self-directed learning approaches were utilized. The pilot psychedelic psychopharmacology elective was a success, providing a framework for future courses. [ABSTRACT FROM AUTHOR]

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2–0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness. [ABSTRACT FROM AUTHOR]

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT 2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNF α) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNF α. • A single dose of psychedelic [(R)-DOI] promotes Escape in stress-susceptible mice. • A low dose of [(R)-DOI] improves stress resilient behavior. • Social stress in the Stress Alternatives model increases plasma and neural TNF α. • Stress-induced elevation of cytokine expression in BLA in Stay susceptible phenotype. • A low dose of [(R)-DOI] reduces social stress-induced TNF α in BLA. [ABSTRACT FROM AUTHOR]

• Pigs respond to 0.08 mg/kg psilocybin i.v. with headshakes, scratching and rubbing behaviour. • A similar dose produce a cerebral 5-HT 2A receptor occupancy of ~67%. • 1 week after psilocybin exposure an immunology-related genetic response was seen in prefrontal cortex. Psilocybin has in some studies shown promise as treatment of major depressive disorder and psilocybin therapy was in 2019 twice designated as breakthrough therapy by the U.S. Food and Drug Administration (FDA). A very particular feature is that ingestion of just a single dose of psilocybin is associated with lasting changes in personality and mood. The underlying molecular mechanism behind its effect is, however, unknown. In a translational pig model, we here present the effects of a single dose of psilocybin on pig behaviour, receptor occupancy and gene expression in the brain. An acute i.v. injection of 0.08 mg/kg psilocybin to awake female pigs induced characteristic behavioural changes in terms of headshakes, scratching and rubbing, lasting around 20 min. A similar dose was associated with a cerebral 5-HT 2A receptor occupancy of 67%, as determined by positron emission tomography, and plasma psilocin levels were comparable to what in humans is associated with an intense psychedelic experience. We found that 19 genes were differentially expressed in prefrontal cortex one day after psilocybin injection, and 3 genes after 1 week. Gene Set Enrichment Analysis demonstrated that multiple immunological pathways were regulated 1 week after psilocybin exposure. This provides a framework for future investigations of the lasting molecular mechanisms induced by a single dose of psilocybin. In the light of an ongoing debate as to whether psilocybin is a safe treatment for depression and other mental illnesses, it is reassuring that our data suggest that any effects on gene expression are very modest. [ABSTRACT FROM AUTHOR]

Objective: The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD).Methods: Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports.Results: Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS.Conclusions: Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies. [ABSTRACT FROM AUTHOR]

• Only one serious adverse event was reported during psychedelic experience. • Most side effects occur only in the hours following intake. • There is a possible dose-effect relationship concerning side effects. • Psychedelics are safe in a controlled setting with appropriate inclusion criteria. Psychotherapies assisted by psychedelic substances have shown promising results in the treatment of psychiatric disorders. The aim of this systematic review and meta-analysis was to evaluate safety data in human subjects. We carried out a search on MEDLINE, Embase and PsycINFO databases between 2000 and 2022. Standardized mean differences between different dose ranges and between acute and subacute phases were calculated for cardiovascular data after psychedelic administration. Risk differences were calculated for serious adverse events and common side effects. Thirty studies were included in this meta-analysis. There were only nine serious adverse events for over 1000 administrations of psychedelic substances (one during the acute phase and 8 during the post-acute phase). There were no suicide attempts during the acute phase and 3 participants engaged in self-harm during the post-acute phase. There was an increased risk for elevated heart rate, systolic and diastolic blood pressure for all dose range categories, as well as an increased risk of nausea during the acute phase. Other common side effects included headaches, anxiety, and decreased concentration or appetite. This meta-analysis demonstrates that psychedelics are well-tolerated, with a low risk of emerging serious adverse events in a controlled setting with appropriate inclusion criteria. [ABSTRACT FROM AUTHOR]

Psychedelic-assisted therapy is based on the premise that psychedelic substances can act as catalysts or adjuncts to psychotherapeutic processes. Recent clinical trials involving psychedelic-assisted therapy have generally employed a similar three-part structure consisting of preparation, support during the dosing sessions, and subsequent "integration." However, the content of these sessions and the frame through which the therapists approach participants and understand the clinical process has thus far been inconsistent among studies. In designing a manualized therapy protocol for a small clinical trial of psilocybin-assisted therapy for major depressive disorder, our group sought to delineate an explicit and replicable, evidence-based model that intentionally builds upon both the neurobiological actions of the medication and the phenomenology of the drug experience. Having identified considerable concordance in proposed mechanisms of change between Acceptance and Commitment Therapy (ACT) and psilocybin therapy, we employed ACT as an overarching psychotherapeutic framework. We hypothesize that the psilocybin experience can provide direct experiential contact with ACT processes that increase psychological flexibility, and that these deeply felt experiences may in turn be reinforced during ACT-informed follow-up therapy sessions. In this paper, we describe the rationale for selecting ACT, areas of potential synergism between ACT and psilocybin-therapy, the basic structure of our treatment model, and limitations to this approach. • Psychedelic-assisted therapies have potential in a variety of mental disorders. • Psilocybin therapy and ACT are synergistic as both foster psychological flexibility. • The psilocybin experience can provide experiential contact with core ACT processes. • Psilocybin-assisted therapy of depression may be optimized by integrating ACT. [ABSTRACT FROM AUTHOR]

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT 2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT 2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT 2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT 2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT 2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT 2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT 2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT 2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT 2A receptors, and additional experiments are needed to elucidate the role of 5-HT 2A receptors in the behavioral and clinical effects of carvedilol. • Computational chemistry to identified critical ligand structural features of 5-HT 2A receptor binding • Carvedilol was identified as a priority match for binding. • Carvedilol has high nanomolar affinity for 5-HT 2A receptors. • The selective 5-HT 2A receptor antagonist M100907 attenuated behavioral effects of carvedilol. • These data suggest a novel mechanism of action for carvedilol. [ABSTRACT FROM AUTHOR]

Ayahuasca is a beverage used in Amazonian traditional medicine and it has been part of the human experience for millennia as well as other different psychoactive plants. Although Ayahuasca has been proposed as potentially therapeutic as an anxiolytic and antidepressant, whilst no studies have been carried out so far investigating their direct effect on brain emotional processing. This study aimed to measure the emotional acute effect of Ayahuasca on brain response to implicit aversive stimulation using a face recognition task in functional magnetic resonance imaging (fMRI). Nineteen male experienced Ayahuasca users participated in this study in two fMRI sessions before and after 50 min of the Ayahuasca ingestion. Subjects were presented with pictures of neutral (A) and aversive (B) (fearful or disgusted) faces from the Pictures of Facial Affect Series. Subjects were instructed to identify the gender of the faces (gender discrimination task) while the emotional content was implicit. Subjective mood states were also evaluated before Ayahuasca intake and after the second fMRI session, using a visual analogue mood scale (VAMS). During the aversive stimuli, the activity in the bilateral amygdala was attenuated by Ayahuasca (qFDR<0.05). Furthermore, in an exploratory analysis of the effects after intake, Ayahuasca enhances the activation in the insular cortex bilaterally, as well as in the right dorsolateral prefrontal cortex (qFDR<0.05). In the psychometric VAMS scale, subjects reported attenuation of both anxiety and mental sedation (p < 0.01) during acute effects. Together, all reported results including neuroimaging, behavioral data and psychometric self-report suggest that Ayahuasca can promote an emotion regulation mechanism in response to aversive stimuli with corresponding improved cognition including reduced anxiety and mental sedation. [Display omitted] • Ayahuasca is a psychedelic of Amazonian origin with cerebral serotonergic action. • Ayahuasca use by experienced users reveal brain and behavioral changes. • Ayahuasca acts on emotional regulation that could explain its therapeutic potential. [ABSTRACT FROM AUTHOR]

Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT 2A R) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT 2A R agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT 2A R and 5-HT 1A R agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression. • Psychedelic drug DOI did not show prophylactic effect in LPS-treated mice. • Non-hallucinogenic psychedelic analog lisuride did not show prophylactic effect in LPS-treated mice. • Arketamine, the (R)-enantiomer of ketamine, showed prophylactic effect in LPS-treated mice. [ABSTRACT FROM AUTHOR]

Summary Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo . These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders. [ABSTRACT FROM AUTHOR]

Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. A small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms. [ABSTRACT FROM AUTHOR]

Evidence suggests that psychedelics may serve as a therapeutic approach to reduce substance use; however, people with racial and ethnic minoritized (REM) identities are often excluded from this research. We investigated whether psychedelic use affects other substance use among REM people and whether perceived changes in psychological flexibility and racial trauma mediates this association. REM people in the United States and Canada (N = 211; 32 % Black, 29 % Asian, 18 % American Indian/Indigenous Canadian, 21 % Native Hawaiian/Pacific Islander; 57 % female; mean age = 33.1, SD = 11.2) completed an online survey retrospectively reporting their substance use, psychological flexibility, and racial trauma symptoms 30 days before and after their most memorable psychedelic experience. Analyses showed a significant perceived reduction in alcohol (p <.0001, d = 0.54) and drug use (p =.0001, d = 0.23) from before to after the psychedelic experience. Preliminary associations found perceived reductions in racial trauma symptoms were associated with perceived reductions in alcohol use and this association varied by race, dose, ethnic identity, and change in depressive symptoms. Specifically, Indigenous participants experienced greater perceived reductions in alcohol use relative to participants who identified as Asian, Black, or other. Those who took a high dose of psychedelics experienced greater perceived reductions in alcohol use relative to those who took a low dose. Participants with a stronger ethnic identity and those with a perceived reduction in depressive symptoms experienced a perceived reduction in alcohol use. Serial mediation indicated a perceived increase in psychological flexibility and reduction in racial trauma symptoms mediated the association between acute psychedelic effects and perceived reductions in alcohol and drug use. These findings suggest that psychedelic experiences may contribute to an increase in psychological flexibility and reduction in racial trauma symptoms and alcohol and drug use among REM people. REM people have been largely excluded from psychedelic treatment research even though psychedelic use is considered a traditional healing practice in many communities of color. Longitudinal studies of REM people should replicate our findings. • Psychedelic treatment may reduce mental health and substance use problems. • People of Color (POC) are underrepresented in psychedelic research. • We investigated the impact of psychedelics on substance use outcomes among POC. • Psychedelic use was associated with reductions in alcohol and other drug use. • Racial trauma symptoms and psychological flexibility were significant mediators. [ABSTRACT FROM AUTHOR]

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT 2A , and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT 2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT 2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT 2A β-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT 2A -selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications. [Display omitted] • 2-Br-LSD is a 5-HT 2A partial agonist but lacks 5-HT 2B agonism • 2-Br-LSD lacks head-twitch responses and tolerance; blocks psychedelics • 2-Br-LSD treatment promotes neuronal structural plasticity dependent on 5-HT 2A • 2-Br-LSD produces active coping behavior and reverses chronic stress deficits Lewis et al. perform an extensive pharmacological characterization of 2-Br-LSD, finding distinct aminergic GPCR polypharmacology, including 5-HT 2A partial agonism and lack of psychedelic-like effects in vivo. Further, 2-Br-LSD induces dendritogenesis and spinogenesis in vitro while promoting active coping behavior in vivo , effects dependent on 5-HT 2A activation. [ABSTRACT FROM AUTHOR]

Research on classical psychedelics (psilocybin, LSD and DMT) and entactogen, MDMA, has produced a renaissance in the search for more effective drugs to treat psychiatric, neurological and various peripheral disorders. Psychedelics and entactogens act though interaction with 5-HT 2A and other serotonergic receptors and/or monoamine reuptake transporters. 5-HT, which serves as a neurotransmitter and hormone, is ubiquitously distributed in the brain and peripheral organs, tissues and cells where it has vasoconstrictor, pro-inflammatory and pro-nociceptive actions. Serotonergic psychedelics and entactogens have known safety and toxicity risks. For these drugs, the risks been extensively researched and empirically assessed through human experience. However, novel drug-candidates require thorough non-clinical testing not only to predict clinical efficacy, but also to address the risks they pose during clinical development and later after approval as prescription medicines. We have defined the challenges researchers will encounter when developing novel serotonergic psychedelics and entactogens. We describe screening techniques to predict clinical efficacy and address the safety/toxicity risks emerging from our knowledge of the existing drugs: 1) An early-stage, non-clinical screening cascade to pharmacologically characterise novel drug-candidates. 2) Models to detect hallucinogenic activity. 3) Models to differentiate hallucinogens from entactogens. 4) Non-clinical preclinical lead optimisation technology (PLOT) screening to select drug-candidates. 5) Modified animal models to evaluate the abuse and dependence risks of novel psychedelics in Safety Pharmacology testing. Our intention has been to design non-clinical screening strategies that will reset the balance between benefits and harms to deliver more effective and safer novel psychedelics for clinical use. This article is part of the Special Issue on 'National Institutes of Health Psilocybin Research Speaker Series'. • A novel, non-clinical, screening strategy to characterise novel psychedelics and entactogens. • Animal models to detect hallucinogenic activity. • Non-clinical techniques to differentiate hallucinogenic psychedelics from entactogens. • Preclinical lead optimisation technology (PLOT) to identify drug-candidates. • Animal models optimised to assess the abuse/dependence potential of psychedelics and entactogens. [ABSTRACT FROM AUTHOR]

Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT 2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was <6.5 s, and responding on lever B was reinforced if the interval was >6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point ( T 50 ) and the Weber fraction (a measure of timing precision). The 5-HT 2A antagonist M100907 increased T 50 , whereas the 5-HT 2C antagonist SB-242,084 reduced T 50 . The results indicate that 5-HT 2A and 5-HT 2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT 2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T 50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT 2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T 50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT 2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits observed in schizophrenia and other psychiatric disorders. [ABSTRACT FROM AUTHOR]

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75 µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC–visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context. [ABSTRACT FROM AUTHOR]

Monoamine oxidase inhibitors (MAOIs) are often ingested together with tryptamine hallucinogens, but relatively little is known about the consequences of their combined use. We have shown previously that monoamine oxidase-A (MAO-A) inhibitors alter the locomotor profile of the hallucinogen 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) in rats, and enhance its interaction with 5-HT 2A receptors. The goal of the present studies was to investigate the mechanism for the interaction between 5-MeO-DMT and MAOIs, and to determine whether other behavioral responses to 5-MeO-DMT are similarly affected. Hallucinogens disrupt prepulse inhibition (PPI) in rats, an effect typically mediated by 5-HT 2A activation. 5-MeO-DMT also disrupts PPI but the effect is primarily attributable to 5-HT 1A activation. The present studies examined whether an MAOI can alter the respective contributions of 5-HT 1A and 5-HT 2A receptors to the effects of 5-MeO-DMT on PPI. A series of interaction studies using the 5-HT 1A antagonist WAY-100,635 and the 5-HT 2A antagonist MDL 11,939 were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in rats pretreated with an MAOI. The effects of MAO-A inhibition on the pharmacokinetics of 5-MeO-DMT and its metabolism to bufotenine were assessed using liquid chromatography–electrospray ionization–selective reaction monitoring–tandem mass spectrometry (LC-ESI-SRM-MS/MS). 5-MeO-DMT (1 mg/kg) had no effect on PPI when tested 45-min post-injection but disrupted PPI in animals pretreated with the MAO-A inhibitor clorgyline or the MAO-A/B inhibitor pargyline. The combined effect of 5-MeO-DMT and pargyline on PPI was antagonized by pretreatment with either WAY-100,635 or MDL 11,939. Inhibition of MAO-A increased the level of 5-MeO-DMT in plasma and whole brain, but had no effect on the conversion of 5-MeO-DMT to bufotenine, which was found to be negligible. The present results confirm that 5-MeO-DMT can disrupt PPI by activating 5-HT 2A , and indicate that MAOIs alter 5-MeO-DMT pharmacodynamics by increasing its accumulation in the central nervous system. [ABSTRACT FROM AUTHOR]

• Hallucinations are one of the most interesting and least understood human experience. • Early scientific research on hallucinogen drugs such as LSD was criticised and then withdrawn, but its recent revival offers new opportunities to examine the 'process of hallucinating.' • When carefully conducted in emotionally stable individuals in controlled and supervised settings, psychedelic research opens new avenues of research to expose the processes and origins of hallucinations. 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. [ABSTRACT FROM AUTHOR]

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT 2A R) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT 2A R in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT 2A R agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT 2A R and 5-HT 1A R agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT 2A R-related psychedelic effects. It is, therefore, unlikely that 5-HT 2A R may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed. • Psychedelic drug DOI did not show antidepressant-like effect in LPS-treated mice. • Non-hallucinogenic psychedelic analog lisuride shows antidepressant-like effect in LPS-treated mice. • DOI did not ameliorate the decreased dendritic spine density in the brain of LPS-treated mice. • Lisuride ameliorated the decreased dendritic spine density in the brain of LPS-treated mice. • Antidepressant effect of lisuride is not associated with 5-HT 2A R-related psychedelic effects. [ABSTRACT FROM AUTHOR]

• An easy-to-use LC-MS/MS method for DMT and its two major metabolites was developed. • The method allows sensitive analyte quantification and rapid sample measurement. • The endogenously occurring metabolite IAA was quantified using 13C 6 -IAA calibrations. • Only small volumes of plasma (50 μL) are required for sample analysis. The indole alkaloid N , N -dimethyltryptamine (DMT) induces psychedelic effects in humans. In addition to ceremonial and recreational use, DMT is subject to clinical investigations. Sensitive bioanalytical methods are required to assess the pharmacokinetics of DMT and its metabolites in human plasma. Here, a high performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the quantification of DMT and its major metabolites indole-3-acetic acid (IAA) and DMT- N -oxide (DMT-NO) was developed and validated. As IAA is an endogenous component of human plasma, 13C 6 -IAA was used to determine IAA concentrations. After simple protein precipitation with methanol, analytes were separated on a pentafluorophenyl column. A gradient consisting of 0.1% (v/v) formic acid in a methanol–water mixture was applied for analyte separation. The analytes were detected by positive electrospray ionization followed by multiple reaction monitoring. The calibration range of the assay was 0.25–250 ng/mL for DMT, 0.1–100 ng/mL for DMT-NO, and 25–25,000 ng/mL for 13C 6 -IAA. The intra- and inter-assay accuracy was 93–113% for all analytes at all quality control levels, with coefficient of variation ≤ 11%. All analytes were stable under storage conditions relevant for the analysis of large batches of study samples. The validated method was capable of assessing pharmacokinetic (PK) parameters of DMT and its metabolites in study participants intravenously perfused with 1 mg/min DMT for 90 min. Overall, the developed method is easy-to-use, has a short run time, and qualifies for PK and metabolism studies of DMT in clinical settings. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that classic psychedelics (5-HT 2A receptor agonists or partial agonists) such as psilocybin might facilitate behavior change in individuals with substance use disorders. We conducted a multi-site, double-blind, randomized controlled trial (RCT) to assess the effects of psilocybin-assisted psychotherapy in alcohol-dependent volunteers. In addition to a structured 12-week psychotherapy platform, participants (n = 96) were randomly assigned (1:1) to receive either oral psilocybin or an active placebo (oral diphenhydramine) in each of two dosing sessions (at weeks 4 and 8). Initial doses were 25 mg/70 kg psilocybin or 50 mg diphenhydramine, which could be increased in the second session depending on initial response. The psychotherapy platform combined evidence-based, manualized therapy for alcohol dependence with a supportive context for the dosing sessions. All participants were followed in the RCT through week 36. At the end of the RCT, participants who still met safety criteria were offered an open-label psilocybin session. Data collected at screening, baseline and throughout the study included: demographics, measures of alcohol use, subjective response to psilocybin and diphenhydramine, and safety measures. The primary outcome was the proportion of heavy drinking days during the 32 weeks after the first dosing session (i.e., between week 4 and week 36). Secondary outcomes included safety, additional measures of drinking (e.g., abstinence, drinking days, etc.), craving, self-efficacy, and acute effects. We will also explore moderators and mediators of the primary outcome. The primary outcomes will be published elsewhere. In this paper, we describe the protocol and rationale for our design decisions. [ABSTRACT FROM AUTHOR]

N , N -Diallyltryptamine (DALT) and 5-methoxy- N , N -diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12–20 mg range, while the unsubstituted compound DALT had few discernible effects in the 42–80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10–80 nM range for serotonin 5-HT 1A and 5-HT 2B receptors, while the affinity of DALT itself at 5-HT 1A receptors was slightly lower at 100 nM. Among the 5-HT 2 subtypes, the weakest affinity was at 5-HT 2A receptors, spanning 250–730 nM. Five of the DALT compounds had affinity in the 50–400 nM range for serotonin 5-HT 1D , 5-HT 6 , and 5-HT 7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT 1B , 5-HT 1E , and 5-HT 5A subtypes and little or no affinity for the 5-HT 3 subtype. These compounds also had generally nanomolar affinities for adrenergic α 2A , α 2B , and α 2C receptors, sigma receptors σ 1 and σ 2 , histamine H 1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure–affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic ( σ p ), hydrophobic ( π ), and steric (CMR) parameters. The binding affinity at 5-HT 1A , 5-HT 1D , 5-HT 7 , and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α 2A , α 2B , and α 2C receptors, and at the histamine H 1 receptor, binding affinity was correlated with the Hammett substituent parameter σ p ; higher affinity was associated with larger σ p values. At the σ 2 receptor, higher affinity was correlated with increasing π . These correlations should aid in the development of more potent and selective drugs within this family of compounds. [ABSTRACT FROM AUTHOR]

There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and may potentially receive full FDA approval with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical use of psychedelic medicines, the status of the empirical evidence, and numerous significant policy considerations that must be thoughtfully addressed regarding standards-of-practice, consumer protection, engagement of communities, safeguarding access for all, and developing data standards, which supports the responsible, accountable, safe, and ethical uses of these medicines in clinical, faith-based, and other contexts. We provide suggestions for how public health and harm reduction can be supported through a public-private partnership that engages a community of stakeholders from various disciplines in the co-creation and dissemination of best practices and public policies. • Psychedelics carry notable promise and risk when used as mental health therapies. • Public education and facilitator training are essential for risk mitigation. • Public policies must prioritize harm reduction and best practices. • Successful scaling up of psychedelic therapies requires equitable access. [ABSTRACT FROM AUTHOR]

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT 2A receptor is the primary site of hallucinogen action. The 5-HT 2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a debilitating mental illness with limited treatment options and a high treatment dropout rate. Psychedelics, often in combination with psychotherapy, are now under investigation as a potential treatment option for a variety of psychiatric conditions including PTSD. This paper reviews the proposed mechanism of action for 3,4-Methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin in treating PTSD, along with available clinical evidence, safety and side effects. MDMA-assisted psychotherapy is in FDA phase III clinical trials for PTSD and is purported to work by way of increased empathy and decreased amygdala activation during the therapeutic encounter and trauma processing. Classical psychedelics may create change by a subjective transformative experience along with an observable process of brain network alterations, though these substances have not been clinically studied in the context PTSD. In recent human-subject studies MDMA-assisted therapy resulted in significant improvement in PTSD symptoms with a good safety and side effect profile. There is not yet direct clinical evidence for classical psychedelics in treating PTSD, but the evidence supports such a trial. The studies to date have been relatively small, and participants are wellscreened for potential co-morbidities which could increase the risks of psychedelic treatment. Nonetheless, the data is promising for psychedelic-assisted treatment to become a much-needed treatment option for PTSD. • Emerging models of the neurological and psychological effects of psychedelics provide support for their potential use in PTSD • MDMA-assisted therapy has a robust effect on PTSD symptoms with relatively minor side effects in the population studied • There is adequate evidence to support direct clinical study of psilocybin-assisted therapy for the treatment of PTSD • Safety data on psychedelics is reassuring to date, and likely to change as clinicians and patients grow in number & diversity [ABSTRACT FROM AUTHOR]

Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic imaging researchers, review the 42 research articles published to date, based on the 17 unique studies evaluating psychedelic effects on rs-fMRI, focusing on methodological variation. Prominently, we observe that nearly all studies vary in data processing and analysis methodology, two datasets are the foundation of over half of the published literature, and there is lexical ambiguity in common outcome metric terminology. We offer guidelines for future studies that encourage coherence in the field. Psychedelic rs-fMRI will benefit from the development of novel methods that expand our understanding of the brain mechanisms mediating its intriguing effects; yet, this field is at a crossroads where we must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics. [Display omitted] • Psychedelic resting-state brain imaging has grown immensely over the past decade. • To date, forty-two papers from seventeen unique datasets have been reported. • Variations across the field in data processing and analysis limit replicability. • An alignment in analysis methods is timely given the description of recent novel datasets. • This paper offers guidelines to balance novel methods and replication in the field. [ABSTRACT FROM AUTHOR]

Background: Iboga and its primary alkaloids, ibogaine and noribogaine, have been of interest to researchers and practitioners, mainly due to their putative efficacy in treating substance use disorders (SUDs). For many SUDs, still no effective pharmacotherapies exist. Distinct psychoactive and somatic effects of the iboga alkaloids set them apart from classic hallucinogens like LSD, mescaline, and psilocybin.Aims: The study team performed this systematic review focusing on clinical data and therapeutic interventions involving ibogaine and noribogaine.Methods: The team conducted a search for all publications up to December 7, 2020, using PubMed and Embase following PRISMA guidelines.Results: In total, we identified 743 records. In this review, we consider 24 studies, which included 705 individuals receiving ibogaine or noribogaine. This review includes two randomized, double-blind, controlled clinical trials, one double-blind controlled clinical trial, 17 open-label studies or case series (including observational or retrospective studies), three case reports, and one retrospective survey. The published data suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and craving. Data also point toward a beneficial impact on depressive and trauma-related psychological symptoms. However, studies have reported severe medical complications and deaths, which seem to be associated with neuro- and cardiotoxic effects of ibogaine. Two of these fatalities were described in the 24 studies included in this review.Conclusion: Treatment of SUDs and persisting comorbidities requires innovative treatment approaches. Rapid-onset therapies such as the application of ibogaine may offer novel treatment opportunities for specific individuals. Rigorous study designs within medical settings are necessary to warrant safe application, monitoring, and, possibly, medical intervention. [ABSTRACT FROM AUTHOR]

Abstract: N-benzyl substitution markedly enhances the affinity of phenethylamine hallucinogens at the 5-HT2A receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT2A receptor activation in rats and mice, and is widely used as a behavioral proxy for hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1–10 mg/kg SC), 25I-NBOMe (0.1–1 mg/kg SC), and 25I-NBMD (1–10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT2A antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine hallucinogens induce the HTR by activating 5-HT2A receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT2A affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these hallucinogens will become more widespread in the future. [Copyright &y& Elsevier]

Abstract: Background: Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache. Methods: This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30mg/70kg) on headache in 18 healthy participants. Results: Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration. Conclusions: Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research. [Copyright &y& Elsevier]

Abstract: Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375μg/kg to 21μg/kg. Subject-rated drug strength was assessed every 2min for 60min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2min (first time point) and definite subjective effects were no longer present at approximately 20min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2A) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects. [Copyright &y& Elsevier]

Abstract: Background: Between 2002 and 2005 fresh or unprepared psilocin-based ‘magic’ mushrooms were legal to possess and traffic in the UK, and commercial sales demonstrated a significant market for this hallucinogenic drug. During and after this time there has been relatively little analysis concerning how magic mushroom users accounted for their drug use, nor on the wider political and cultural discourses that might have shaped this sense making. Method: In this paper we present a critical analysis of contemporary discourses around magic mushroom use in the UK through a multi-level discourse analysis of focus group data from 20 magic mushroom users (13 male and 7 female, mean age 25 years), taken at a time when magic mushrooms were being legally sold in the UK. Results: Locating participants’ use of magic mushrooms within the context of a culture of intoxication, neo-liberalism and the legacy of 1960s psychedelic philosophy, we identify six interpretative repertoires in their talk, which were subsumed within two overarching discourses. The first discourse drew on neo-liberal rhetoric, constructing participants as rational risk managing subjects engaged in a form of calculated hedonism that was legitimated as an act of personal freedom and consumer choice. The second discourse, identified as ‘post-psychedelic’, both celebrated and problematised a collective, connected ‘hippy’ form of spirituality. Conclusion: The paper analyses the relationships between identity, consumption and citizenship by arguing that people''s ability to imagine collectivist, spiritual or interconnected social worlds has been contained within neo-liberalism rhetoric. [Copyright &y& Elsevier]