Poster No:
2627
Submission Type:
Abstract Submission
Authors:
Mihai Avram1, Lydia Fortea2, Felix Müller3, Lea Wollner1, Ricarda Coennen1, Alexandra Korda1, Helena Rogg1, Friederike Holze4, Patrick Vizeli3, Anna Becker3, Laura Ley3, Joaquim Radua2, Matthias Liechti3, Stefan Borgwardt1
Institutions:
1University of Lübeck, Lübeck, Germany, 2University of Barcelona, Barcelona, Spain, 3University Hospital Basel, Basel, Switzerland, 4Neurobiology Research Unit, Rigshospitalet, Copenhagen, Hovestaden
First Author:
Co-Author(s):
Friederike Holze
Neurobiology Research Unit, Rigshospitalet
Copenhagen, Hovestaden
Anna Becker
University Hospital Basel
Basel, Switzerland
Laura Ley
University Hospital Basel
Basel, Switzerland
Introduction:
Psychedelics have garnered considerable attention due to their potential to alleviate symptoms of various psychiatric disorders (1,2,3). Despite therapeutic promise, their precise neurobiological mechanisms underlying such effects remain incompletely understood.
Comparing psychedelics with substances having partly overlapping neurophysiological effects could provide valuable insights into their mechanisms of action. This comparison forms the basis of our investigation, which discusses the findings from two independent studies derived from clinical trials NCT03019822 and NCT04227756. The former study compared the effects of LSD to d-amphetamine and MDMA, while the latter compared LSD to other psychedelics, namely psilocybin and mescaline.
Methods:
Both studies employed a randomized, double-blind, placebo-controlled, cross-over design to compare the acute effects in healthy volunteers (study 1: n=25, mean age 28±4 years, 14 women; Study 2: n=26, mean age 27.5±2.6 years, 13 women) (4,5). Functional MRI data, assessed during peak effects, were acquired on the same MRI scanner with the same sequence and were preprocessed with the same pipeline using C-PAC (6). We used a network parcellation approach (7) to investigate connectivity within-network (integrity), between-network (segregation), and globally (i.e., degree centrality; DC). Between-group differences were investigated with repeated-measures ANOVAs, followed by post-hoc pairwise t-tests. Statistical analyses conducted in R, underwent correction for multiple comparisons (FDR).
Results:
In study 1, LSD reduced integrity in the visual (VIS), default mode (DMN), and frontoparietal networks (FPN), compared to placebo. The amphetamines reduced integrity in auditory-sensorimotor (ASM), salience (SAL), FPN, and VIS, but not in DMN. LSD findings were largely replicated in study 2, with integrity decreases in DMN and VIS, compared to placebo. Psilocybin reduced integrity in VIS and trend-wise DMN, while mescaline reduced integrity in VIS and DMN, albeit to a lesser extent than LSD.
Regarding segregation, in study 1, LSD produced more pronounced effects (i.e., decreases) compared to placebo than the amphetamines but similar effects as the other psychedelics in study 2. Unlike the amphetamines, no increase in segregation was observed for any psychedelic. Direct comparisons revealed no differences between LSD and psilocybin, but LSD showed more extensive connectivity than mescaline and the latter more extensive connectivity than psilocybin.
Regarding global connectivity, in study 1, LSD increased DC compared to placebo in basal ganglia, thalamus, and auditory cortices. Compared to placebo, d-amphetamine and MDMA increased DC in small clusters covering dorsolateral prefrontal cortex and fusiform gyrus, respectively. LSD increased DC in sensorimotor areas compared to both amphetamines. In study 2, the LSD vs. placebo findings were replicated among additional clusters found in sensorimotor cortices and cerebellum. Psilocybin also increased DC in sensorimotor areas, cerebellum, and middle cingulum. Mescaline did not increase DC compared to placebo. All substances decreased DC in visual areas compared to placebo, with additional decreases in sensorimotor areas for amphetamines and in posterior cingulate/precuneus for psychedelics, respectively.
Conclusions:
We found profound changes in connectivity following the administration of distinct psychoactive compounds. A specific decrease in DMN integrity was observed following psychedelics. While psychedelics only decreased segregation, some increases were observed for amphetamines. LSD increased global connectivity in the basal ganglia and thalamus, aligning with prior reports (8). These outcomes significantly contribute to our understanding of psychedelics' specific impacts on various brain networks, shedding light on their unique neurobiological effects and paving the way for further exploration into their therapeutic potential.
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Perception, Attention and Motor Behavior:
Consciousness and Awareness
Physiology, Metabolism and Neurotransmission :
Pharmacology and Neurotransmission
Physiology, Metabolism and Neurotransmission Other 1
Keywords:
FUNCTIONAL MRI
Neurotransmitter
Pharmacotherapy
Seretonin
Other - Psychedelics
1|2Indicates the priority used for review
Provide references using author date format
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2. Holze, F., Gasser, P., Müller, F., Dolder, P. C., & Liechti, M. E. (2023). Lysergic acid diethylamide–assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study. Biological Psychiatry, 93(3), 215-223.
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