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.
Pharmacologic challenges with tryptamine hallucinogen substances have been used as models for psychosis. In recent years, many studies have used substances to study the neuronal correlates of altered states of consciousness. A current research trend involves testing the effects of hallucinogens as potential therapeutic alternatives for psychiatric disorders. Here we aimed to perform a quantitative meta-analysis of neuroimaging studies in this field. The current work summarizes the level of (in) consistency between functional imaging outcomes from connectivity and activation studies that might help to further clarify the implication of previous reports and their importance concerning the therapeutic potential of these drugs.
The relation between psychedelic experience and psychosis remains intriguing. Sensory hallucinations and attentional deficits are common manifestations in schizophrenia and other neuropsychiatric disorders. The neural correlates of visual and auditory alertness in these conditions have been a matter of study. The approach of experimentally inducing states of psychosis was proven to be very useful to understand the effects of distinct substances in the brain in the so–called pharmacological fMRI approach. In particular, neuroimaging studies have investigated the neural correlates of alertness based on agonistic modulation of the human serotonin 2A receptor (5-HT2AR, 5-hydroxytryptamine2A) (using dimethyltryptamine-DMT) and N-methyl-D-aspartic acid (NMDA) antagonism (using ketamine) for psychosis. Moreover, 5-HT2AR activation through LSD has been implicated in the formation of visual hallucinations and cognitive impairments. 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. This substance is a preferential serotonin (5-HT) 2A/1A receptor agonist. Psilocybin, reduces the processing of negative stimuli which is relevant concerning affective processing in the amygdala. This emotion-processing structure is particularly prone to serotonergic modulation. Psilocybin-induced decrease in amygdala reactivity correlates with and reduces threat-induced modulation of amygdala activation and/or connectivity.
Other hallucinogens inducing similar effects have been used to study the rapid changes in brain dynamics and functional connectivity (FC) in neuroimaging, regarding the quality of conscious experience in the psychedelic state. These substances include Lysergic acid diethylamide (LSD) that induces profound changes across various mental domains, including perception, self-awareness and emotional state; or Ayahuasca, that is a beverage traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. Ayahuasca caused significant decreases in the activity and connectivity of the default mode network (DMN) and increased excitability in multimodal brain areas as the posterior association cortex, the cingulate, and the Medial temporal lobe (MTL), that are pivotal in interoception and emotional processing.
Psychedelic drugs such as LSD were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Accordingly, the use of these substances may have important implications for the treatment of depression, mood and anxiety disorders. Additionally, the current literature also emphasizes the importance of 5-HT2A/1A receptor subtypes in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses. Here we provide a comprehensive review of studies in this field. Our findings suggest important implications for the understanding of the mechanism of action of hallucinogenic drugs and provide further insight into the role of these substances to improve mental health, pain or neurodegenerative disorders.
We performed the literature search using the PubMed database in Sep/2020. The search criteria were: LSD (Title/Abstract) OR lysergic (Title/Abstract) OR psilocybin (Title/Abstract) OR ayahuasca (Title/Abstract) OR dimethyltryptamine (Title/Abstract) AND [fMRI (Title/Abstract) OR BOLD (Title/Abstract) OR PET (Title/Abstract)]. Figure 1 (PRISMA) summarizes the number of articles and duplicates that were found. To identify functional brain imaging studies, our inclusion criteria were: 1) the studies imaged the whole brain; 2) the results presented coordinate-based data in a standard space and were not review papers; 3) the imaging method was fMRI or PET; 4) subjects were healthy controls; 5) sample size N ≥ 8.
From the initial identification of 78 studies, the final study included 16 fMRI studies and four PET studies (Table 1) reporting brain imaging experiments related to those drugs. We then used the foci of brain activations extracted from each of the included studies for the ALE analysis.
Summary of studies included in the review. The studies detail and individual res
