Abstract
There is an increasing interest in the neural effects of psychoactive drugs, in particular tryptamine psychedelics, which has been incremented by the proposal that they have potential therapeutic benefits, based on their molecular mimicry of serotonin. It is widely believed that they act mainly through 5HT2A receptors but their effects on neural activation of distinct brain systems are not fully understood. We performed a quantitative meta-analysis of brain imaging studies to investigate the effects of substances within this class (e.g., LSD, Psilocybin, DMT, Ayahuasca) in the brain from a molecular and functional point of view. We investigated the question whether the changes in activation patterns and connectivity map into regions with larger 5HT1A/5HT2A receptor binding, as expected from indolaemine hallucinogens (in spite of the often reported emphasis only on 5HT2AR). We did indeed find that regions with changed connectivity and/or activation patterns match regions with high density of 5HT2A receptors, namely visual BA19, visual fusiform regions in BA37, dorsal anterior and posterior cingulate cortex, medial prefrontal cortex, and regions involved in theory of mind such as the surpramarginal gyrus, and temporal cortex (rich in 5HT1A receptors). However, we also found relevant patterns in other brain regions such as dorsolateral prefrontal cortex. Moreover, many of the above-mentioned regions also have a significant density of both 5HT1A/5HT2A receptors, and available PET studies on the effects of psychedelics on receptor occupancy are still quite scarce, precluding a metanalytic approach. Finally, we found a robust neuromodulatory effect in the right amygdala. In sum, the available evidence points towards strong neuromodulatory effects of tryptamine psychedelics in key brain regions involved in mental imagery, theory of mind and affective regulation, pointing to potential therapeutic applications of this class of substances.
Highlights
Pharmacologic challenges with tryptamine hallucinogen substances have been used as models for psychosis
Neuroimaging studies have investigated the neural correlates of alertness based on agonistic modulation of the human serotonin 2A receptor (5HT2AR, 5-hydroxytryptamine2A) and N-methyl-D-aspartic acid (NMDA) antagonism for psychosis (Daumann et al, 2010)
The profound experience induced by psychedelics like DMT, Ayahuasca, Lysergic acid diethylamide (LSD) and Psilocybin is characterized by changes in emotion, perception and cognition, visual imagery and differences in the sense of self (Swanson, 2018; Barrett et al, 2020b; Lowe et al, 2021; Luppi et al, 2021)
Summary
Pharmacologic challenges with tryptamine hallucinogen substances have been used as models for psychosis. Neuroimaging studies have investigated the neural correlates of alertness based on agonistic modulation of the human serotonin 2A receptor (5HT2AR, 5-hydroxytryptamine2A) (using dimethyltryptamineDMT) and N-methyl-D-aspartic acid (NMDA) antagonism (using ketamine) for psychosis (Daumann et al, 2010). The psychedelic experience produced by psilocybin (Psi) (a substance found in “magic mushrooms”) is characterized by “unconstrained” cognition and profound alterations in the perception of time, space and selfhood (Mason et al, 2021). This substance is a preferential serotonin (5-HT) 2A/1A receptor agonist (Halberstadt and Geyer, 2011). Psilocybin-induced decrease in amygdala reactivity correlates with and reduces threat-induced modulation of amygdala activation and/or connectivity (Kraehenmann et al, 2015, Kraehenmann et al, 2016; Preller et al, 2017; Barrett et al, 2020b)
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