This meta-analysis (2021) of brain imaging studies finds that under the influence of psychedelics (tryptamines), the most changes in connectivity are indeed the ones where there are the most 5-HT1a/2a receptors. Other regions are also highlighted, and these regions most influenced are responsible for mental imagery, theory of mind, and affective regulation.

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.”

Authors: Joao M. Castelhano, Gisela M. Lima, Marta Teixeira, Carla Soares, Marta Pais & Miguel Castelo-Branco

Summary

INTRODUCTION

A recent research trend involves testing the effects of hallucinogens as potential therapeutic alternatives for psychiatric disorders. This meta-analysis summarizes the level of consistency between functional imaging outcomes from connectivity and activation studies.

The relation between psychedelic experience and psychosis remains intriguing. Neuroimaging studies have investigated the neural correlates of visual and auditory alertness in schizophrenia and other neuropsychiatric disorders, and have implicated 5-HT2AR activation through LSD in the formation of visual hallucinations and cognitive impairments.

Other hallucinogens such as Lysergic acid diethylamide (LSD) or Ayahuasca 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.

Psychedelic drugs were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. This review suggests that these drugs may have important implications for the treatment of depression, mood and anxiety disorders.

Search Strategy and Data Sources

We searched the PubMed database for studies on LSD, psilocybin, ayahuasca, dimethyltryptamine, and fMRI using the following criteria: whole brain imaging, coordinate-based data in a standard space, and healthy controls.

Data Extraction

We converted all foci data to MNI standard space and discussed all the available PET studies in a narrative manner, given the insight they provide on molecular mechanisms of action.

ALE Analysis

ALE meta-analysis was performed using GingerALE (v3.0.2) and the MNI image template (Kochunov et al., 2002). The statistical significance of the results was assessed using a permutation test.

We performed an analysis of all fMRI papers with BOLD and connectivity results and two separate analyses with connectivity results. The results were converted to Z scores and overlaid on activation maps.

RESULTS

A total of 323 subjects participated in 98 BOLD studies and 76 connectivity studies on LSD, Psilocybin, Ayahuasca and DMT.

We performed a systematic review of PET studies in the field and found only four studies that passed the inclusion criteria. These studies reported results for distinct PET tracers namely (18F) DG and (11C) Cimbi-36, and only the latter was related to 5-HT2AR, a serotonin receptor for which there is wide evidence for psychoactive drug effects.

The concept that 5-HT2AR is the main neurotransmitter involved in indoleamine/tryptamine hallucinogens has been challenged.

PET studies focused on the effects of Psilocybin, which decreased 5-HT2AR receptor occupancy and density. This does not preclude actions in other neurotransmitter systems, including the D2 dopamine receptor.

Psilocybin increases metabolism in the anterior cingulate and thalamus in 18-FDG studies, suggesting that these regions share a sizable density of both 5-HT1A and 5-HT2A receptors.

Amygdala and Emotional Effects and Anxiety

The results show that the amygdala is deactivated during the psychedelic induced states, which might underlie the emotional effects of these substances. This effect may be of clinical relevance in disorders associated with difficulties in emotional processing such as depression, anxiety and addiction. Although there are no conclusive findings on the lateralization of amygdala in emotional processing, some studies point to different activations. These include hyperactivation of the right amygdala in patients with PTSD and obsessive-compulsive disorder. Research indicates that healthy populations show a reduced amygdala response to facial stimuli 1-week post-psilocybin, returning to baseline after 1 month.

Salience Network and Pain, Psychiatric and Neurological Disorders

The dorsal anterior cingulate cortex is involved in attributing salience to sensory stimuli and selecting relevant interoceptive, autonomic and emotional stimuli. This network is also involved in psychosis and autism spectrum disorder.

Theory of Mind and Social Cognition

We found relevant patterns in regions involved in theory of mind, such as supramarginal gyrus, medial prefrontal cortex, precuneus and posterior cingulate cortex, and suggested that the modulation of social cognition may be an important mechanism contributing to the therapeutic potential of psychedelics.

LSD-induced states increased functional connectivity in the bilateral temporo-parietal junction, a key component of theory of mind, which was correlated to subjective reports of ego dissolution. This increase was associated with increased emotional empathy and prosocial behaviour, as well as feelings of connection to others.

Mental Imagery

The activation of visual areas by psychedelics induced substances, namely visual areas BA19 and visual fusiform region BA37, was another outcome of our quantitative meta-analysis. These areas are densely populated with 5-HT2A receptors, which are involved in visual processes and the pathogenesis of visual hallucinations. Recent studies demonstrated that acute LSD administration to healthy subjects produces elementary and complex visual hallucinations and perceptual illusions, as well as impaired inhibitory processes and cognitive organization. These effects were attenuated by administration of the 5-HT2AR antagonist ketanserin.

Psychedelics can cause cognitive impairments by disrupting inhibitory cortico-striato-thalamocortical feedback loops, which can lead to high-level processing overload and the formation of hallucinations.

Ayahuasca increased activations in mental imagery networks, including early visual areas, parahippocampal gyrus, middle temporal cortex, and frontal cortex, and primary visual cortex was preceding activation patterns in higher-level areas. The perceptual alterations of simple and elementary visual features as color, brightness, visual contrast, as well as complex imagery and hallucinations have been reported. These images are usually very structured, thematic and personal. Studies have reported that neuronal stimulation of PFC, temporal areas and primary visual cortex causes visual hallucinations. Furthermore, psychedelics increase introspection and positive mood by modulating brain activity in the fronto-temporo-parietooccipital cortices.

The amygdala plays an important role in visual processing, and may have a contextual role during visual coding. It is deactivated during psychedelic induced states, and may have a therapeutic potential.

Default Mode Network

Tryptamine psychedelics may affect the Default Mode Network (DMN), which is involved in internal mental processes such as autobiographical memory, mind wandering, self-reflective thought, and future thinking.

In our analysis, we observed decreased connectivity within PCC/Precuneus, key components of the DMN, in subjects taking psilocybin, LSD, and ayahuasca. Barrett et al. (2020b) proposed that psilocybin alters default mode network integrity and fronto-parietal network modularity by reducing Claustrum functional connectivity with these circuits. This result supports the theory that psilocybin decreases the control of top-down structures and increases the excitability of areas involved in sensory, emotional and cognitive appraisal processes.

Functional connectivity between the DMN and the Frontoparietal Network and the Salience Network is increased in creative thinking and long-term increases in novelty of generated ideas, but is also increased in depression, acute and chronic pain, schizophrenia, Parkinson’s disease and eating disorders.

Linking Molecular Imaging and Functional Magnetic Resonance Imaging Data

There were few eligible pharmacoimaging studies using PET, but two studies using FDG and one using Cimbi-36 suggested a role for the 5-HT2AR receptor subtype. However, a specific link with this receptor system is probably an overstatement.

Therapeutic Potential

Taken together, our results support the plausibility of further research on the therapeutic potential of tryptamine psychedelics in several psychiatric disorders, including posttraumatic stress disorder, treatment-resistant depression, substance addictions, obsessive-compulsive disorder, anxiety associated with life-threatening diseases, and social anxiety in autistic adults.

Psychedelics have shown promising results in several studies, but more research is needed to better understand the neurobiological and psychological mechanisms of action and the potential risks underlying the therapeutic action of tryptamine psychedelics.

LIMITATIONS

This analysis includes studies with small sample sizes, unequal gender distribution and no control group, but all studies included placebo control groups and the data reported are comparisons of drugs vs placebo effects.