Effects Of Lysergic Acid Diethylamide Research Articles

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.

Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT2A) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT1A), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT2A and (2) potent agonism at 5-HT1A. The in vitro effects of lisuride, LSD, and related analogues on 5-HT2A signaling were characterized by using miniGαq and β-arrestin 2 recruitment assays. The 5-HT1A- and 5-HT2A-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT2A, with high efficacy and potency for recruiting miniGαq and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6-52% of 5-HT or LSD Emax) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED50 = 0.039 mg/kg), while lisuride suppresses HTRs (ED50 = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED50 = 0.008-0.023 mg/kg) that was blocked by the 5-HT1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT1A prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT1A agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT1A agonist in C57BL/6J mice, limiting its use as a 5-HT2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.

Effects of External Stimulation on Psychedelic State Neurodynamics.

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

LSD-induced changes in the functional connectivity of distinct thalamic nuclei

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing. The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. Mean (95% confidence interval) maximal LSD concentrations were 1.8ng/mL (1.6-2.0) and 3.4ng/mL (3.0-3.8) after the administration of 85 and 170 μg LSD, respectively. Maximal concentrations were achieved on average after 1.7h. Elimination half-lives were 3.7h (3.4-4.1) and 4.0h (3.6-4.4), for 85 and 170 μg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3±3.2 and 11 ±3.7h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 μg of LSD, respectively. The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery.

Understanding the effects of lysergic acid diethylamide and the importance of its prevention

Understanding the effects of lysergic acid diethylamide and the importance of its prevention

Lysergic acid diethylamide stimulates cardiac human H2 histamine and cardiac human 5-HT4-serotonin receptors

Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT4 serotonin receptors and/or H2 histamine receptors. We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) or of the H2-histamine receptor (H2-TG). For comparison, we used wild type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium obtained from patients during bypass surgery. LSD (up to 10 µM) concentration dependently increased force of contraction and beating rate in left or right atrial preparations from 5-HT4-TG (n = 6, p < 0.05) in 5-HT4-TG atrial preparations. The inotropic and chronotropic effects of LSD were antagonized by 10 µM tropisetron in 5-HT4-TG. In contrast, LSD (10 µM) increased force of contraction and beating rate in left or right atrial preparations, from H2-TG. After pre-stimulation with cilostamide (1 µM), LSD (10 µM) increased force of contraction in human atrial preparations (n = 6, p < 0.05). The contractile effects of LSD in human atrial preparations could be antagonized by 10 µM cimetidine and 1 µM GR 125487. LSD leads to H2-histamine receptor and 5-HT4-receptor mediated cardiac effects in humans.

Effect of LSD and music on the time-varying brain dynamics

RationalePsychedelics are getting closer to being widely used in clinical treatment. Music is known as a key element of psychedelic-assisted therapy due to its psychological effects, specifically on the emotion, meaning-making, and sensory processing. However, there is still a lack of understanding in how psychedelics influence brain activity in experimental settings involving music listening.ObjectivesThe main goal of our research was to investigate the effect of music, as a part of “setting,” on the brain states dynamics after lysergic acid diethylamide (LSD) intake.MethodsWe used an open dataset, where a group of 15 participants underwent two functional MRI scanning sessions under LSD and placebo influence. Every scanning session contained three runs: two resting-state runs separated by one run with music listening. We applied K-Means clustering to identify the repetitive patterns of brain activity, so-called brain states. For further analysis, we calculated states’ dwell time, fractional occupancy and transition probability.ResultsThe interaction effect of music and psychedelics led to change in the time-varying brain activity of the task-positive state. LSD, regardless of the music, affected the dynamics of the state of combined activity of DMN, SOM, and VIS networks. Crucially, we observed that the music itself could potentially have a long-term influence on the resting-state, in particular on states involving task-positive networks.ConclusionsThis study indicates that music, as a crucial element of “setting,” can potentially have an influence on the subject’s resting-state during psychedelic experience. Further studies should replicate these results on a larger sample size.

Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants

There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as “candyflipping.” The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD + MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (Cmax and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD + MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD + MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100 mg) did not improve acute effects or the safety profile of LSD (100 µg). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity

Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomised, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed predominantly stronger interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of weakened interregional connectivity and increased self-inhibition in occipital brain regions as well as subcortical regions. Together, these findings suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Notably, whole-brain EC did not only provide additional mechanistic insight into the effects of LSD on the Excitation/Inhibition balance of the brain, but EC also correlated with global subjective effects of LSD and discriminated experimental conditions in a machine learning-based analysis with high accuracy (91.11%), highlighting the potential of using whole-brain EC to decode or predict subjective effects of LSD in the future.

Prepulse inhibition of the acoustic startle reflex impairment by 5-HT2A receptor activation in the inferior colliculus is prevented by GABAA receptor blockade in the pedunculopontine tegmental nucleus

The relationship between serotonin dysfunction and schizophrenia commenced with the discovery of the effects of lysergic acid diethylamide (LSD) that has high affinity for 5-HT2A receptors. Activation of these receptors produces perceptual and behavioural changes such as illusions, visual hallucinations and locomotor hyperactivity. Using prepulse inhibition (PPI) of the acoustic startle, which is impaired in schizophrenia,we aimed to investigate:i) the existence of a direct and potentially inhibitory neural pathway between the inferior colliculus (IC) and the pedunculopontine tegmental nucleus (PPTg) involved in the mediation of PPI responses by a neural tract tracing procedure;ii) if the microinjection of the 5-HT2A receptors agonist DOI in IC would activate neurons in this structure and in the PPTg by a c-Fos protein immunohistochemistry study;iii) whether the deficits in PPI responses, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of the GABAA receptor antagonist bicuculline in the PPTg.Male Wistar rats were used in this study. An IC-PPTg reciprocated neuronal pathway was identified by neurotracing. The number of c-Fos labelled cells was lower in the DOI group in IC and PPTg, suggesting that this decrease could be due to the high levels of GABA in both structures. The concomitant microinjections of bicuculline in PPTg and DOI in IC prevented the PPI deficit observed after the IC microinjection of DOI. Our findings suggest that IC 5-HT2A receptors may be at least partially involved in the regulation of inhibitory pathways mediating PPI response in IC and PPTg structures.

Lysergic Acid Diethylamide Alters the Effects of Brain Stimulation in Rodents

Background: Psychedelic drugs have resurged in neuroscience and psychiatry with promising success in psychedelic-assisted therapy for the treatment of anxiety, depression, and addiction. At the cellular level, psychedelic drugs elicit neuroplastic processes 24 h after administration, priming neural circuits for change. The acute effects of psychedelic drugs are well characterized with functional imaging and neural oscillations showing an increase in the entropy of spontaneous cortical activity. Hypotheses: We hypothesized that cortical–striatal oscillations recorded in rats would confirm the effects of psychedelic drugs. We also hypothesized that brain stimulation delivered 24 h after lysergic acid diethylamide (LSD) administration would lead to different effects than brain stimulation alone. Methods: We recorded local field potential oscillations from rats after LSD or saline (SAL) administration and determined whether exposure to these treatments altered the effect of a targeted intervention (brain stimulation) 24 h later. Results: We confirmed acutely decreased low frequency power across the brain when rats are given LSD. We also demonstrated these altered states return to baseline after 24 h. Brain stimulation applied in the previously reported window of heightened neuroplasticity produced distinct shifts in brain state compared with brain stimulation applied 24 h after SAL administration. Conclusions: Despite the acute effects of LSD disappearing after 24 h, there are still latent effects that interact with brain stimulation to create larger and distinct changes in brain activity compared with brain stimulation alone. Our proof-of-concept findings are the first to suggest that psychedelic drugs could work in combination with brain stimulation to achieve enhanced effects on brain activity and future study will assess impacts on stimulation-induced changes in behavior.

LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics

A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be modeled by pairwise maximum entropy Ising models at various distances from a phase transition, i.e., from criticality. Here we aim to characterize two brain states (psychedelics-induced and placebo) as captured by functional magnetic resonance imaging (fMRI), with features derived from the Ising spin model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. We hypothesized, along the lines of the entropic brain hypothesis, that psychedelics drive brain dynamics into a more disordered state at a higher Ising temperature and increased complexity. We analyze resting state blood-oxygen-level-dependent (BOLD) fMRI data collected in an earlier study from fifteen subjects in a control condition (placebo) and during ingestion of lysergic acid diethylamide (LSD). Working with the automated anatomical labeling (AAL) brain parcellation, we first create "archetype" Ising models representative of the entire dataset (global) and of the data in each condition. Remarkably, we find that such archetypes exhibit a strong correlation with an average structural connectome template obtained from dMRI (r = 0.6). We compare the archetypes from the two conditions and find that the Ising connectivity in the LSD condition is lower than in the placebo one, especially in homotopic links (interhemispheric connectivity), reflecting a significant decrease of homotopic functional connectivity in the LSD condition. The global archetype is then personalized for each individual and condition by adjusting the system temperature. The resulting temperatures are all near but above the critical point of the model in the paramagnetic (disordered) phase. The individualized Ising temperatures are higher in the LSD condition than in the placebo condition (p = 9 × 10-5). Next, we estimate the Lempel-Ziv-Welch (LZW) complexity of the binarized BOLD data and the synthetic data generated with the individualized model using the Metropolis algorithm for each participant and condition. The LZW complexity computed from experimental data reveals a weak statistical relationship with condition (p = 0.04 one-tailed Wilcoxon test) and none with Ising temperature (r(13) = 0.13, p = 0.65), presumably because of the limited length of the BOLD time series. Similarly, we explore complexity using the block decomposition method (BDM), a more advanced method for estimating algorithmic complexity. The BDM complexity of the experimental data displays a significant correlation with Ising temperature (r(13) = 0.56, p = 0.03) and a weak but significant correlation with condition (p = 0.04, one-tailed Wilcoxon test). This study suggests that the effects of LSD increase the complexity of brain dynamics by loosening interhemispheric connectivity-especially homotopic links. In agreement with earlier work using the Ising formalism with BOLD data, we find the brain state in the placebo condition is already above the critical point, with LSD resulting in a shift further away from criticality into a more disordered state.

LSD reduces anxiety symptoms in Phase 2 trial

The effort to identify alternative treatments for anxiety has led to research into the potential of lysergic acid diethylamide (LSD) in reducing anxiety symptoms. Based on results of a placebo‐controlled pilot study showing that two high doses of LSD in patients with a life‐threatening illness resulted in reductions in anxiety for up to 2 months, investigators conducted a Phase 2 study to evaluate the effects of LSD on anxiety in patients both with and without a life‐threatening illness. The study recruited adults aged 25 and older with an anxiety disorder or significant anxiety associated with a life‐threatening illness. Among those excluded were individuals with a history of a psychotic or bipolar disorder and those with a current substance use disorder. Participants in the crossover study were randomized to two sessions of LSD 200 µg or placebo over two 24‐week treatment periods, with the treatment sessions separated by 6 weeks and with each treatment period including five study visits involving use of talk therapy. The primary outcome was change in Spielberger's State‐Trait Anxiety Inventory‐Global (STAI‐G) score from baseline to 16 weeks after the last treatment session. Forty‐two individuals were randomized to treatment; 20 of the 42 had a life‐threatening illness. LSD resulted in significant reductions in STAI‐G scores compared with placebo. Maximum effects were observed 2 weeks after the second LSD session and were sustained up to 16 weeks. Sixty‐five percent of the LSD group and 9% of the placebo group showed clinical response at an outcome visit, with response defined as at least a 30% reduction in STAI‐G score. LSD also resulted in rapid and sustained improvement in depressive symptoms. Only one serious adverse event in the LSD group was attributed to treatment, involving a participant who experienced anxiety and delusions during a session. The researchers concluded that the results suggest long‐term benefits of LSD‐assisted therapy for anxiety, adding that larger trials should be conducted to confirm these findings. [Holze F, et al. Biol Psychiatry 2022; published online Sep 5; doi: 10.1016/j.biopsych.2022.08.025]

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans.

The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans. Healthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating ('learning rates') and deployment of value representations ('reinforcement sensitivity') during choice, as well as 'stimulus stickiness' (choice repetition irrespective of reinforcement history). Raw data measures assessing sensitivity to immediate feedback ('win-stay' and 'lose-shift' probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase. Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

The use of classic psychedelics among adults: a Danish online survey study

Background Clinical studies report preliminary therapeutic effects of classic psychedelic drugs in several psychiatric conditions and international drug trends show increased use of these compounds. However, the epidemiology of classic psychedelic drug use in Scandinavian countries remains sparsely investigated. To this end, we investigated the patterns of use and the subjectively perceived acute and persisting effects of lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), and mescaline, among Danish adults. Methods An anonymous online survey with 152 items was conducted using the secure survey web application REDCap. Results were presented descriptively and as comparisons between psychedelic drugs. Results Five-hundred participants (30.0% female, mean age 34.5 years) were included. Classic psychedelics were mostly used with therapeutic (28.0%) or spiritual (27.2%) intentions. Sixty-seven per cent used classic psychedelics once a year or less. Most participants (56.4%) preferred using psilocybin. Classic psychedelic use was for some individuals, associated with hazardous use of alcohol (39.4%). Among participants with a psychiatric treatment history, 80.9% reported subjective improvements in symptoms following classic psychedelic use. Participants’ most memorable experiences were moderate-to-strong mystical-type experiences (MEQ30 mean ± SD 3.4 ± 1.0; range 1–5) and had positive persisting effects on well-being (mean ± SD 2.1 ± 1.0), social relationships (mean ± SD 1.7 ± 1.2), meaning of life (mean ± SD 1.9 ± 1.1), and mood (mean ± SD 1.8 ± 1.1); range −3 to 3. DMT users experienced significantly greater subjective positive effects. Conclusions Classic psychedelics were mostly used therapeutically or spiritually and had self-reported positive persisting effects, but were also associated with hazardous use of alcohol, among Danish adults. DMT was associated with significantly greater positive effects compared to LSD and psilocybin.

Effective Connectivity of Functionally Anticorrelated Networks Under Lysergic Acid Diethylamide

BackgroundClassic psychedelic-induced ego dissolution involves a shift in the sense of self and a blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network, which directs attention inward, and the salience network, which recruits the dorsal attention network to direct attention outward. MethodsTo test whether changes in anticorrelated networks underlie the peak effects of lysergic acid diethylamide (LSD), we applied dynamic causal modeling to infer effective connectivity of resting-state functional magnetic resonance imaging scans from a study of 25 healthy adults who were administered 100 μg of LSD or placebo. ResultsWe found that inhibitory effective connectivity from the salience network to the default mode network became excitatory, and inhibitory effective connectivity from the default mode network to the dorsal attention network decreased under the peak effect of LSD. ConclusionsThe effective connectivity changes we identified may reflect diminution of the functional anticorrelation between resting-state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest that changes to the sense of self and subject-object boundaries across different states of consciousness may depend upon the organized balance of effective connectivity of resting-state networks.

Adverse experiences resulting in emergency medical treatment seeking following the use of lysergic acid diethylamide (LSD).

Background:Recreational lysergic acid diethylamide (LSD) use is growing in popularity amid increasing research interest on psychedelics and their possible therapeutic potential yet; the potent psychotropic effects of LSD may result in adverse reactions and behaviour.Aims:This study aimed to investigate the 12-month incidence and nature of LSD-related adverse experiences resulting in emergency medical treatment (EMT) seeking in an international sample of people reporting LSD use.Methods:We use data from the 2017 Global Drug Survey – a large anonymous online survey on patterns of drug use conducted between November 2016 and January 2017.Results:Out of 10,293 past-year LSD users, 102 (1.0%) reported seeking EMT, with a per-event risk estimate of 0.2%. Younger age, comorbid mental health conditions and higher frequency of use were associated with increased risk of EMT seeking. The most common symptoms were psychological, including anxiety, panic and confusion, with the most common explanatory factors cited by respondents being poor ‘setting’ and ‘mindset’. Most responders reported feeling back to normal within 24 h, but 11 participants experienced persistent issues after 4 weeks.Conclusion:The results suggest that LSD is a relatively safe drug in recreational settings. Adverse reactions are typically short-lived, self-limiting and psychological in nature. Sub-optimal set and setting were commonly reported as suspected contributory factors. Within clinical settings, patient screening, preparatory sessions and supervision should reduce these acute risks considerably.

Effect of -NBOMe Compounds on Sensorimotor, Motor, and Prepulse Inhibition Responses in Mice in Comparison With the 2C Analogs and Lysergic Acid Diethylamide: From Preclinical Evidence to Forensic Implication in Driving Under the Influence of Drugs.

In the last decade, the market for new psychoactive substances has been enriched by numerous psychedelic phenethylamines, which mimic the psychoactive effect of lysergic acid diethylamide (LSD). In particular, the -NBOMe series, which are more potent than their 2C compounds analogs, are considered worthy substitutes for LSD by users. The purpose of this study was to assess the effects of 25H-NBOMe and its halogenated derivatives (25I-NBOMe and 25B-NBOMe) in comparison to their 2C compounds analogs and LSD on the sensorimotor (visual, acoustic, and overall tactile), reaction time, spontaneous (total distance traveled) and stimulated (drag, accelerod test) motor activity, grip strength test, and prepulse inhibition (PPI) responses in mice. Systemic administration of -NBOMe, 2C compounds analogs, and LSD (0.001–10 mg/kg) differently impaired the sensorimotor, reaction time, motor, and PPI responses in mice. In particular, halogenated (25I and 25B)-NBOMe derivatives appear to be more effective than the entire class of 2C compounds analogs in altering visual and acoustic responses, affecting reaction time, and motor and sensory gating in PPI test. In fact, the specific rank order of compounds potency for nearly all of the experiments showed that (25I and 25B)-NBOMe were more potent than 2C compounds analogs and LSD. -NBOMe and 2C compounds analogs impaired not only the reception of incoming sensory stimuli (visual and acoustic), but their correct brain processing (PPI) in an equal and sometimes stronger way than LSD. This sensory impairment directly affected the spontaneous motor response and reaction time of mice, with no change in performance in stimulated motor activity tests. These aspects should be carefully considered to better understand the potential danger that psychedelic phenethylamines, in particular -NBOMe, may pose to public health, with particular reference to decreased performance in driving and hazardous works that require special sensorimotor skills.

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744