This double-blind, placebo-controlled, crossover trial (n=28) finds that LSD (100μg), d-amphetamine (40mg), and MDMA (125mg) reduced network integrity in healthy volunteers. LSD uniquely reduced default-mode network integrity and showed more pronounced effects on network segregation and seed-based connectivity compared to amphetamines.
Abstract of Large-scale brain connectivity changes following the administration of LSD, d-amphetamine, and MDMA
“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.”
Authors: Mihai Avram, Lydia Fortea, Lea Wollner, Ricarda Coenen, Alexandra Korda, Helena Rogg, Friederike Holze, Patrick Vizeli, Laura Ley, Joaquim Radua, Felix Müller, Matthias E. Liechti & Stefan Bordwardt
Summary of Large-scale brain connectivity changes following the administration of LSD, d-amphetamine, and MDMA
Psychedelic compounds, particularly substances like lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT), have garnered significant attention due to their potential to reduce symptoms associated with various psychiatric disorders, such as depression, anxiety, and addiction. Despite their therapeutic promise, the precise mechanisms underlying psychedelic effects on the human brain remain incompletely understood. Comparing psychedelics with distinct substances having partly overlapping neurophysiological effects could shed light on the complex mechanisms of action of these compounds.
The researchers utilised resting-state functional magnetic resonance imaging (rs-fMRI) to explore the impact of three distinct compounds: LSD, d-amphetamine, and MDMA on brain connectivity patterns. Despite these compounds’ unique psychological effects and disparate actions on neurotransmitter systems, there are notable overlapping outcomes. LSD, which can induce profound alterations in visual and auditory perceptions, audiovisual synesthesia, derealization, and depersonalization, primarily exerts its influence as a partial agonist at the serotonergic 2A receptor (5-HT2AR). MDMA is characterized by its capacity to enhance feelings of well-being and induce mild perceptual alterations, and relies predominantly on serotonergic neurotransmission. D-amphetamine, a compound with distinct psychological effects, including euphoria, changes in sexual desire, increased wakefulness, and improved cognitive control, elevates dopaminergic activity through its interactions with the dopamine transporter and dopamine release.
The study aimed to investigate and compare the effects of LSD, d-amphetamine, and MDMA on three key aspects: (1) network integrity and segregation based on resting-state network (RSN) templates, (2) network-dependent changes in whole-brain intrinsic functional connectivity (iFC), using a voxel-wise seed-based approach, and (3) global connectivity changes, assessed through degree centrality (DC). The researchers hypothesized that LSD would reduce the integrity of several RSNs compared to placebo, with more pronounced effects in the default mode network (DMN). They expected MDMA to elicit similar changes in network integrity as LSD, but weaker effects for d-amphetamine. Similarly, they anticipated network segregation to be more reduced for all substances compared to placebo across RSNs but more pronounced for LSD than MDMA and d-amphetamine, respectively.
Materials and Methods
Participants and Study Design
Find this paper
https://doi.org/10.1038/s41380-024-02734-y
Open Access | Google Scholar | Backup | 🕊
Cite this paper (APA)
Avram, M., Fortea, L., Wollner, L., Coenen, R., Korda, A., Rogg, H., ... & Borgwardt, S. (2024). Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3, 4-methylenedioxyamphetamine. Molecular Psychiatry, 1-11.
Study details
Topics studied
Healthy Subjects
Neuroscience
Study characteristics
Original Re-analysis
Placebo-Controlled
Double-Blind
Within-Subject
Randomized
Participants
25
Humans
Compound Details
The psychedelics given at which dose and how many times
LSD 100 μg | 1x MDMA 125 mg | 1xLinked Research Papers
Notable research papers that build on or are influenced by this paper
MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogensThis double-blind, placebo-controlled, fMRI study (n=45) found that MDMA induced similar (neuronal) changes as classical (serotonergic) psychedelics.
Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects
This placebo-controlled, randomized, double-blind, cross-over study (n=28) investigated distinct acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg) in healthy subjects. The results show that LSD, MDMA and D-amphetamine had different ratings on the 5 Dimensions of Altered States of Consciousness scale (5DASC) and Mystical Experience Questionnaire (MEQ). It also clearly indicates the distinct neurological and behavioral profiles of LSD, MDMA and D-amphetamine.
Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration
This re-analysis of a double-blind, placebo-controlled, crossover study (n=25) investigated the effects of LSD, MDMA and dextroamphetamine on brain measures (thalamocortical and corticothalamic interactions in resting-state fMRI data). Compared to placebo, all three substances increased the effective-connectivity from the thalamus to specific unimodal cortices while reducing their influence on the thalamus, revealing increased bottom-up and decreased top-down information flow; LSD uniquely increased effective-connectivity to both unimodal and transmodal cortices.
Linked Clinical Trial
Role of Dopamine, Serotonin and 5-HT2A Receptors in Emotion ProcessingThe study will test the effect of dopamine, serotonin, and direct 5-HT2A receptor stimulation on empathy, mood perception, and amygdala activity to fearful stimuli.