Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine.
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 Borgwardt
Molecular Psychiatry April 1, 2025 DOI: 10.1038/s41380-024-02734-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 28 |
| Population | Healthy volunteers |
| Interventions | LSD d-amphetamine MDMA |
| Topics | LSD |
| Keywords | Psychedelics hallucinogens Psychoactive drugs Entheogens Brain networks Neural pathways Pharmacology drug effects Drug interactions Psychopharmacology |
| Citations | 26 |
| Registration | NCT03019822 |
| Key findings | LSD uniquely reduces integrity in the default-mode network and increases global connectivity in the basal ganglia and thalamus, distinguishing its effects from amphetamines. |
Abstract
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.
Comparable studies
Other randomized controlled trials on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases Patients with anxiety associated with life-threatening diseases | 2014 | Randomized controlled trial | n = 12 |
| Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users | 1994 | Double-blind, saline placebo-controlled, randomized study | n = 12 |
| Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects Healthy subjects (8 women, 8 men) | 2014 | Double-blind, randomized, placebo-controlled, crossover study | n = 16 |
| Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Healthy human participants | 2018 | Double-blind, randomized, counterbalanced, cross-over study | n = 24 |
| LSD-induced entropic brain activity predicts subsequent personality change. Healthy adults | 2016 | Balanced-order, placebo-controlled study | n = 19 |
Citations in the library
Cited by 22
- The psychedelic-peptide paradox: a hormetic hypothesis. Comprehensive Psychoneuroendocrinology June 2, 2025
- Electrophysiological mechanisms of psychedelic drugs: A systematic review. Neuroscience & Biobehavioral Reviews June 1, 2026
- Psychedelics do not always enhance cognitive flexibility: The potential role of time-varying effects on reward learning processes Neuroscience & Biobehavioral Reviews May 30, 2026
- Neuroplastic white matter changes in patients with major depression following lysergic acid diethylamide treatment Cell Reports Medicine May 7, 2026
- Subjective and neurocognitive profiling of clinical doses of 3,4-methylenedioxymethamphetamine (MDMA) in healthy volunteers: implications for therapeutic use Molecular Psychiatry April 8, 2026
and 17 more in the library
Cites 40
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV) PLoS One August 31, 2010
and 35 more in the library