Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Bedford P

PROVIDER: S-EPMC10267115 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bedford Peter P Hauke Daniel J DJ Wang Zheng Z Roth Volker V Nagy-Huber Monika M Holze Friederike F Ley Laura L Vizeli Patrick P Liechti Matthias E ME Borgwardt Stefan S Müller Felix F Diaconescu Andreea O AO

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20230425 8

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 random ...[more]

PMID: 37185950

Similar Datasets

Project description:The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Project description:Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.

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

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets