Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5- HT2A receptor
Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji, Charles Schleifer, Brendan D. Adkinson, Philipp Stampfli, Erich Seifritz, Grega Repovs, John H. Krystal, John D. Murray, Franz X. Vollenweider, Alan Anticevic
eLife, 2018, 7, e35082.
Background : Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown.
Methods : We therefore conducted a double-blind, randomized, counterbalanced, cross-over study (ClinicalTrials.gov, NCT02451072) during which 24 healthy human participants received either (i)placebo +placebo, (ii) placebo +LSD (100 mg po), or (iii)ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps.
Findings : LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans.
Conclusion : Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoint the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics.
Funding : Swiss National Science Foundation (SNSF, P2ZHP1_161626), the Swiss Neuromatrix Foundation (2015 – 0103), the Usona Institute (2015 – 2056), and the NIH (R01MH112746, JM)
eLife digest The psychedelic drug LSD alters thinking and perception. Users can experience
hallucinations, in which they, for example, see things that are not there. Colors, sounds and objects
can appear distorted, and time can seem to speed up or slow down. These changes bear some
resemblance to the changes in thinking and perception that occur in certain psychiatric disorders,
such as schizophrenia. Studying how LSD affects the brain could thus offer insights into the
mechanisms underlying these conditions. There is also evidence that LSD itself could help to reduce
the symptoms of depression and anxiety disorders.
Preller et al. have now used brain imaging to explore the effects of LSD on the brains of healthy
volunteers. This revealed that LSD reduced communication among brain areas involved in planning
and decision-making, but it increased communication between areas involved in sensation and
movement. Volunteers whose brains showed the most communication between sensory and
movement areas also reported the strongest effects of LSD on their thinking and perception.
Preller et al. also found that another drug called ketanserin prevented LSD from altering how
different brain regions communicate. It also prevented LSD from inducing changes in thinking and
perception. Ketanserin blocks a protein called the serotonin 2A receptor, which is activated by a
brain chemical called serotonin that, amongst other roles, helps to regulate mood. By mapping the
location of the gene that produces the serotonin 2A receptor, Preller et al. showed that the receptor
is present in brain regions that show altered communication after LSD intake, therefore pinpointing
the importance of this receptor in the effects of LSD.
Psychiatric disorders that produce psychotic symptoms affect vast numbers of people worldwide.
Further research into how LSD affects the brain could help us to better understand how such
symptoms arise, and may also lead to the development of more effective treatments for a range of
mental health conditions.
Disorders of perception and the form and content of thought are important contributors to the
global burden of disease (Murray et al., 2012). Mechanistic studies of consciousness may be under-
taken using psychedelic drugs as pharmacologic probes of molecular signaling within cortical net-
works underlying perception and thought. In particular, lysergic acid diethylamide (LSD) is a
psychedelic drug with predominantly agonist activity at serotonin (5-HT)2A/C, -1A/B, -6, and -7
and dopamine D2 and D1 receptors (R). Its administration produces characteristic alterations in perception, mood, thought, and the sense of self (Marona-Lewicka et al., 2002; Nichols, 2004).
Despite its powerful effects on consciousness, human research on LSD neurobiology stalled in the
late 1960 s because of a narrow focus on the experiential effects of hallucinogenic drugs, combined
with a lack of understanding of its effects on molecular signaling mechanisms in the brain. However,
renewed interest in the potentially beneficial clinical effects of psychedelics (Carhart-Harris et al.,
2016a; Gasser et al., 2014; Griffiths et al., 2016) warrants a better understanding of their underly-
ing neuropharmacology. Nevertheless, major knowledge gaps remain regarding LSD’s neurobiology
in humans as well as its time-dependent receptor neuropharmacology.
To address this critical gap, the current study aims to comprehensively map time-dependent pharmacological effects of LSD on neural functional connectivity in healthy human adults and compare them to the spatial expression profile of genes coding for receptors interacting with LSD. The goal is to leverage the statistical properties of the slow (<1 Hz) intrinsic fluctuations of the blood- oxygen-level-dependent (BOLD) signal hemodynamics at rest (i.e. resting-state functional connectivity (rs-fcMRI)). Critically, rs-fcMRI analyses are able to reveal the functional architecture of the brain, which is organized into large-scale systems exhibiting functional relationships across space and time (Biswal et al., 2010; Buckner et al., 2013; Yang et al., 2014a). Rs-fcMRI measures have furthermore revealed potential biomarkers of various neural disorders (Murrough et al., 2016;Yang et al., 2016a), as well as proven sensitive to the effects of neuropharmacological agents (Driesen et al., 2013a; Abdallah et al., 2017).
Focused analyses on specific regions revealed effects of intravenously administered LSD on functional connectivity between V1 and distributed cortical and subcortical regions (Carhart-Harris et al., 2016b). However, such ‘seed-based’ approaches rely on explicitly selecting specificregions of interest based on a priori hypotheses. Therefore, such an approach has limited ability todetect pharmacologically-induced dysconnectivity not predicted a priori. To characterize LSD effectson functional connectivity in the absence of strong a priori hypotheses, the current study employeda fully data-driven approach derived from graph theory called Global Brain Connectivity(GBC) (Anticevic et al., 2014a). In essence, GBC computes the connectivity of every voxel in the brain with all other voxels and summarizes that in asingle value. Therefore, areas of high GBC arehighly functionally connected with other areas and might play a role in coordinating large-scale pat-terns of brain activity (Cole et al., 2010). Reductions in GBC may indicate decreased participation ofa brain area in larger networks, whereas increased GBC may indicate a broadening or synchroniza-tion of functional networks (Anticevic et al., 2014a). One focused study examined GBC after intra-venously administered LSD in a sample of 15 participants, revealing connectivity elevations acrosshigher-order association cortices (Tagliazucchi et al., 2016). While compelling, this preliminary studydid not take into account the influence of global signal (GS) artifacts (e.g. via global signal regres-sion, GSR), which are known to exhibit massive differences in clinical populations and following phar-macological manipulations (Power et al., 2017; Yang et al., 2016b; Lewis et al., 2017;Driesen et al., 2013b). Specifically, GS is hypothesized to contain a complex mixture of non-neuronal artifact (e.g., physiological, movement, scanner-related) (Coyle, 2006), which can induce spuriously high relationships across the brain (Yang et al., 2014a). No study has examined LSD-induced
changes as a function of GS removal. To inform this knowledge gap a major objective here was to study data-driven LSD-induced dysconnectivity in the context of GS removal.
Another aim of the current study was to determine the extent to which the neural and behavioral effects of LSD are mediated by 5-HT2A receptors. Preclinical studies suggest that LSD binds potently to many neuroreceptors including 5-HT2A, 5-HT2C, 5-HT1A, D2, and other receptors (Marona-Lewicka et al., 2002; Passie et al., 2008). Yet, a recent paper from our group (Preller et al., 2017) reported that the psychedelic effects of LSD were entirely blocked in humans by ketanserin, a selective antagonist at 5-HT2A and a-adreno receptors (Leysen et al., 1982). This would suggest that the neural effects of LSD should be blocked by ketanserin. It also suggests that networks modulated by LSD should highly be associated with the distribution of 5- HT2A receptors in the brain and not closely associated with the distribution of receptors unrelated to the mechanism of action of LSD.
Here we leverage recent advances (Burt et al., 2017) in human cortical gene expression mapping to inform the spatial topography of neuropharmacologically-induced changes in data-driven connec-
tivity. We hypothesized that the LSD-induced GBC change will quantitatively match the spatial expression profile of genes coding for the 5-HT2A receptor. In turn, we hypothesized that this effect
will be preferential for the 5-HT2A but not other receptors and that the spatial match will be vastly
improved after artifact removal. In doing so, this convergence of neuropharmacology and gene
expression mapping validates the contribution of the 5-HT2A receptor to LSD neuropharmacology.
In turn, it also highlights a general method for relating spatial gene expression profiles to neuro-
pharmacological manipulations, which has direct and important implications for the rational refine-
ment of any receptor neuropharmacology.
Collectively, this pharmacological neuroimaging study addresses the following major knowledge gaps in our understanding of LSD neurobiology, by demonstrating: (i) data-driven LSD effects across brain-wide networks, which are exquisitely sensitive to GS removal, (ii) the subjective and neural effects of LSD neuropharmacology are attributable to the 5-HT2A receptor, and (iii) the cortex-wide LSD effects can be mapped onto the spatial expression profile of the gene coding for the 5-HT2A receptor.