Seasonal changes in brain serotonin transporter binding in short 5-HTTLPR-allele carriers but not in long-allele homozygotes

Several findings suggest seasonal variations in the serotonin (5-HT) system. We sought evidence for seasonal variation in the serotonin transporter (5-HTT). We found that length of daylight time in minutes correlates negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, but no such association in the midbrain. In the putamen, an anatomical region with a dense serotonin innervation that is implicated in processing of aversive stimuli, we found a significant gene*daylight effect with a negative correlation between the 5-HTT binding and daylight time in carriers of the short 5-HTTLPR allele, but not in carriers of the long allele. The neurobiological endophenotype identified here directly links activation studies, showing responses on the neural circuit level, with dynamic changes in transporter expression measured in vivo

Effects of DMT on mental health outcomes in healthy volunteers.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybins acute effects (4-6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1-2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via Oceanic Boundlessness). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT

Negative affective bias in depression following treatment with psilocybin or escitalopram – a secondary analysis from a randomized trial

Recent clinical trial data suggests that ratings on depression scales are lowered after psilocybin therapy compared to placebo, though it is unclear what neuropsychological mechanisms underpin these effects. This study compared psilocybin, with an established antidepressant, escitalopram, to investigate whether there are shared or distinct effects on emotional information processing. Patients with long-standing moderate-to-severe depression were randomly and double-blindly assigned in a 1:1 ratio to receive either 1) two doses of 25 mg of psilocybin, 3-weeks apart, plus 6-weeks of daily placebo (psilocybin group N = 30); or 2) two doses of 1 mg of psilocybin 3-weeks apart plus 6-weeks of daily oral escitalopram (escitalopram group N = 29); all patients received the same psychological support. Behavioural measures of affective bias as well as subjective measures of depression were collected at baseline and at the primary 6-week endpoint, using an established computerised task (Facial Emotion Recognition Task) and Quick Inventory of Depressive Symptomatology, respectively. Change in affective bias was further correlated with change in depression scores measured concurrently as well as at 1-month post-trial follow-up (week-10), corrected for baseline depression severity. Negative bias in facial expression recognition decreased after both treatments to a comparable level. Concurrently, change in negative affective bias was not associated with change in depression. Longitudinally, a decrease in the misclassification of positive faces as negative was associated with a decrease in depression scores at week-10 for the escitalopram group only. Therefore, a more positive behavioural bias in emotional processing was seen following psilocybin and citalopram compared to baseline. This highlights the potential for at least some overlap in cognitive mechanisms across two distinct treatments, which is noteworthy given the short dosing regimen with psilocybin

Case analysis of long-term negative psychological responses to psychedelics.

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived negative psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe-e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use-and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly severer cases were invited to be interviewed; of these, 15 accepted an in-depth interview that lasted on average 60 min. This sample was 40% male, mean age = 31 ± 7. Five of the 15 (i.e., 33%) reported receiving new psychiatric diagnoses after psychedelic-use and all fifteen reported the occurrence or worsening of psychiatric symptoms post use, with a predominance of anxiety symptoms (93%). Distilling the content of the interviews suggested the following potential causal factors: unsafe or complex environments during or surrounding the experience, unpleasant acute experiences (classic psychedelics), prior psychological vulnerabilities, high- or unknown drug quantities and young age. The current exploratory findings corroborate the reality of mental health iatrogenesis via psychedelic-use but due to design limitations and sample size, cannot be used to infer on its prevalence. Based on interview reports, we can infer a common, albeit multifaceted, causal mechanism, namely the combining of a pro-plasticity drug-that was often over-dosed-with adverse contextual conditions and/or special psychological vulnerability-either by young age or significant psychiatric history. Results should be interpreted with caution due to the small sample size and selective sample and study focus

Membrane permeation of psychedelic tryptamines by dynamic simulations

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activityPID2020-117806GA-I0

Assessing the risk of symptom worsening in psilocybin-assisted therapy for depression: A systematic review and individual participant data meta-analysis.

We conducted a meta-analysis using individual participant data from three, two-dose psilocybin trials for depression (N = 102) with the aim of assessing the risk of symptom worsening. Clinically significant symptom worsening occurred for a minority of participants in the psilocybin and escitalopram conditions (∼10%) and for a majority of participants in the waitlist condition (63.6%). Using data from the two trials with control arms, the psilocybin arm showed a lower likelihood of symptom worsening versus waitlist, and no difference in the likelihood of symptom worsening versus escitalopram. The limitation of a relatively small sample size should be addressed in future studies

Altered Insula Connectivity under MDMA

Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning

Perturbing whole‐brain models of brain hierarchy: An application for depression following pharmacological treatment

Determining the scale of neural representations is a central challenge in neuroscience. While localized representations have traditionally dominated, evidence suggests information is also encoded in distributed, hierarchical networks. Recent research indicates that the hierarchy of causal influences shaping functional patterns serves as a signature of distinct brain states, with implications for neuropsychiatric disorders. Here, we first explore how whole‐brain models, guided by the thermodynamics of mind framework, estimate brain hierarchy and how perturbing such models enables the study of in‐silico transitions represented by static functional connectivity. We then apply this to major depressive disorder, where different brain hierarchical reconfigurations emerge following psilocybin and escitalopram treatments. We build resting‐state whole‐brain models of depressed patients before and after interventions and conduct a dynamic sensitivity analysis to explore brain states’ susceptibility—measuring their capacity to change—and their drivability to healthier states. We show that susceptibility is on average reduced by escitalopram and increased by psilocybin, and that both treatments promote healthier transitions. These results align with the post‐treatment window of plasticity opened by serotonergic psychedelics and the similar clinical efficacy of both drugs in trials. Overall, this work demonstrates how whole‐brain models of brain hierarchy can inform in‐silico neurostimulation protocols for neuropsychiatric disorders

Cortical 5-HT 2A receptors in depression and suicide: a systematic review and meta-analysis of in vivo and post-mortem imaging studies

Introduction: Major depressive disorder (MDD) is a leading cause of suicide and disability. Better understanding changes to serotonin2A receptors (5-HT2ARs) in MDD and suicide may help to improve treatments. We systematically reviewed and meta-analysed positron emission tomography (PET), single photon emission computed tomography (SPECT) and post-mortem radioligand binding studies of cortical 5-HT2ARs in MDD and suicide. Methods: Databases were searched from inception to August/September 2024. Binding data were extracted and pooled before random-effects meta-analyses of mean difference (Hedges’ g) and variance were undertaken. Simple linear regression was performed to investigate the relationship between receptor binding and depression severity at baseline in PET and SPECT studies. We also assessed study quality and tested for evidence of publication bias. Results: Data on 556 MDD patients or suicide victims and 526 controls from 31 studies were included. Cortical 5-HT2AR binding was significantly lower in living MDD patients, who had not taken antidepressants for between one week and forever, than controls in frontal, prefrontal, cingulate, anterior cingulate and, upon sensitivity analysis, temporal cortex (Hedges’ g = –0.40 to –0.57). In frontal and cingulate regions, binding effect size correlated with depression severity at baseline. There was study-level evidence of lower regional binding in never-medicated MDD patients than controls which, upon exploratory meta-analysis, reached significance in anterior cingulate cortex. Most PET or SPECT studies were of good or fair quality. The results of most post-mortem analyses were negative and included studies were of variable quality. There was limited evidence of publication bias. Conclusion: In vivo 5-HT2AR binding is reduced in MDD in frontal, cingulate and temporal cortex. This finding is based mainly on studies that used antagonist or inverse agonist radiotracers

Validation of the imperial psychedelic predictor scale.

BACKGROUND: Access to psychedelic drugs is liberalizing, yet responses are highly unpredictable. It is therefore imperative that we improve our ability to predict the nature of the acute psychedelic experience to improve safety and optimize potential therapeutic outcomes. This study sought to validate the Imperial Psychedelic Predictor Scale (IPPS), a short, widely applicable, prospective measure intended to be predictive of salient dimensions of the psychedelic experience. METHODS: Using four independent datasets in which the IPPS was completed prospectively - two online surveys of naturalistic use (N = 741, N = 836) and two controlled administration datasets (N = 30, N = 28) - we conducted factor analysis, regression, and correlation analyses to assess the construct, predictive, and convergent validity of the IPPS. RESULTS: Our approach produced a 9-item scale with good internal consistency (Cronbachs α = 0.8) containing three factors: set, rapport, and intention. The IPPS was significantly predictive of mystical, challenging, and emotional breakthrough experiences. In a controlled administration dataset (N = 28), multiple regression found set and rapport explaining 40% of variance in mystical experience, and simple regression found set explained 16% of variance in challenging experience. In another (N = 30), rapport was related to emotional breakthrough explaining 9% of variance. CONCLUSIONS: Together, these data suggest that the IPPS is predictive of relevant acute features of the psychedelic experience in a broad range of contexts. We hope that this brief 9-item scale will be widely adopted for improved knowledge of psychedelic preparedness in controlled settings and beyond