Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Preller, Katrin H.; Burt, Joshua B.; Ji, Jie Lisa; Schleifer, Charles; Adkinson, Brendan; Stämpfli, Philipp; Seifritz, Erich; Repovš, Grega; Krystal, John H.; Murray, John D.; Vollenweider, Franz X.; Antičević, Alan

doi:10.7554/elife.35082

Cited by 302 publications

(393 citation statements)

References 71 publications

(132 reference statements)

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“…Several LSD-derived designer drugs induce a head twitch response in mice, and pretreatment with a selective 5-HT 2A receptor antagonist abolished the 1P-LSD-induced head twitch response (Brandt et al 2017a;Brandt et al 2016). This indicates that, similar to LSD, 5-HT 2A receptor activation mediates the behavioral effects of LSD analogs (Kraehenmann et al 2017;Liechti 2017;Preller et al 2017Preller et al , 2018. Additionally, 5-HT 1A receptor activation likely contributes to the qualitative effects of lysergamide designer drugs similarly to LSD and tryptamine psychedelics (Fantegrossi et al 2008;Halberstadt and Geyer 2011;Nichols 2004Nichols , 2016Rickli et al 2016;Winter et al 2000).…”

Section: Mechanism Of Action Of Lysergamidesmentioning

confidence: 95%

“…Traditional psychedelics, such as the phenethylamine 3,4,5trimethoxyphenethylamine (mescaline), the tryptamines N,N-dimethyltryptamine (DMT) and psilocybin, and the ergot alkaloid lysergic acid diethylamide (LSD), have a history of being used for religious purposes, as therapeutic agents, and as illicit black market drugs. Although psychedelics interact with various pharmacological targets, their psychedelic effects are mainly mediated by 5-HT 2A receptor agonism (Geyer and Vollenweider 2008;Kraehenmann et al 2017;Madsen et al 2019;Nichols 2004Nichols , 2016Preller et al 2018;Vollenweider et al 1998). Affinity for 5-HT 2A and 5-HT 2C receptors is correlated with the amount of drug that induces psychedelic effects in humans (Fig.…”

Section: Psychedelicsmentioning

confidence: 99%

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Designer drugs: mechanism of action and adverse effects

2020

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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at l-opioid receptors and c-aminobutyric acid-A (GABA A) or GABA B receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB 1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT 2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

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Section: Mechanism Of Action Of Lysergamidesmentioning

confidence: 95%

Section: Psychedelicsmentioning

confidence: 99%

Designer drugs: mechanism of action and adverse effects

2020

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“…The most robust and reliable neural correlates of the psychedelic experience in humans consist of broadband reductions of spontaneous brain oscillatory activity (especially in the alpha range) and increased signal diversity and complexity, measured with electroencephalography (EEG) and magnetoencephalography (MEG) [4][5][6][7][8][9][10][11]. When measured using functional magnetic resonance imaging (fMRI), psychedelic experiences are associated with global alterations in the functional connectivity between distinct functional networks [10,[12][13][14][15][16]. These changes could be attributed to the activation of layer 5 pyramidal neurons with high density of 5-HT 2A receptors, the main target site of psychedelics [5,[17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Neural and subjective effects of inhaled DMT in natural settings

Pallavicini

Cavanna

Zamberlán

et al. 2020

Preprint

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N,N-Dimethyltryptamine (DMT) is a short acting psychedelic tryptamine found naturally in many plants and animals. When combined with a monoamine oxidase inhibitor, such as in the Amazonian brew known as ayahuasca, DMT becomes orally active and its effects are extended. Few studies to date addressed the neural and psychological effects of DMT alone, either administered intravenously or inhaled in freebase form, and none conducted in natural settings. We combined state-of-the-art wireless electroencephalography (EEG) with psychometric questionnaires to study the acute effects of inhaled DMT in 35 participants in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (known as set and setting), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming DMT in familiar and comfortable settings. We observed that DMT significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. The pharmacokinetics of inhaled DMT was similar to intravenous administration, but we observed a faster return to baseline for power in the alpha band. Gamma power increases correlated with subjective reports indicative of mystical-type experiences. DMT also increased/decreased global synchrony and metastability in the gamma/alpha band, and resulted in widespread increases in signal complexity measured using the Lempel-Ziv algorithm. These results are consistent with previous studies of psychedelic action in the human brain, while at the same time suggesting potential EEG markers of mystical-type experiences in natural settings. In summary, we conducted one of the first field studies on the neural and psychological effects of a serotonergic psychedelic, yielding new insights and advancing our understanding of the translation between laboratory findings and those obtained in the contexts where these compounds are most frequently consumed.

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“…Multiple experiments in humans and animal models have established that the mind-altering effects of psychedelics depend on agonism specifically at the serotonin 2A receptor (5HT2A-R). [15][16][17] A recent simulation study involving whole-brain computational modelling confirmed that the topographic distribution of 5HT2A-R in the human brain is critical to reproduce the functional connectivity dynamics of human fMRI data recorded under the acute effects of LSD. 18 Here we build upon this model to characterise the interplay between the entropy of brain signals, the distribution of 5HT2A receptors, and structural connectivity properties of the brain, with the overarching goal of explaining the sources of entropic effects, and thus altered consciousness, elicited by psychedelic drugs.…”

Section: Introductionmentioning

confidence: 97%

A mechanistic model of the neural entropy increase elicited by psychedelic drugs

Herzog

Mediano

Rosas

et al. 2020

Preprint

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Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, encoding both acute alterations in consciousness and mediating long-term effects. However, no clear mechanistic explanation for this 'entropic' phenomenon has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

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Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Cited by 302 publications

References 71 publications

Designer drugs: mechanism of action and adverse effects

Designer drugs: mechanism of action and adverse effects

Neural and subjective effects of inhaled DMT in natural settings

A mechanistic model of the neural entropy increase elicited by psychedelic drugs

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