Classical hallucinogens and neuroimaging: A systematic review of human studies: hallucinogens and neuroimaging

A systematic review (2016) found that psychedelics (serotonergic ‘hallucinogens’) have a distinct influence on brain structures that have anxiolytic (anxiety-relieving), antidepressant, and antiaddictive properties.

Abstract

“Serotonergic hallucinogens produce alterations of perceptions, mood, and cognition, and have anxiolytic, antidepressant, and antiaddictive properties. These drugs act as agonists of frontocortical 5-HT2A receptors, but the neural basis of their effects is not well understood. Thus, we conducted a systematic review of neuroimaging studies analyzing the effects of serotonergic hallucinogens in man. Studies published in the PubMed, Lilacs, and SciELO databases until 12 April 2016 were included using the following keywords: “ayahuasca”, “DMT”, “psilocybin”, “LSD”, “mescaline” crossed one by one with the terms “mri”, “fmri”, “pet”, “spect”, “imaging” and “neuroimaging”. Of 279 studies identified, 25 were included. Acute effects included excitation of frontolateral/frontomedial cortex, medial temporal lobe, and occipital cortex, and inhibition of the default mode network. Long-term use was associated with thinning of the posterior cingulate cortex, thickening of the anterior cingulate cortex, and decreased neocortical 5-HT2A receptor binding. Despite the high methodological heterogeneity and the small sample sizes, the results suggest that hallucinogens increase introspection and positive mood by modulating brain activity in the fronto-temporo-parieto-occipital cortex.”

Authors: Rafael G. dos Santos, Flávia L. Osório, José Alexandre S. Crippa & Jaime E. C. Hallak

Summary

Serotonergic hallucinogens are used in different human cultures all over the world for ritual and therapeutic purposes. However, use is incidental and transient for most consumers, and prevalence has declined from 4.5 to 0.4% in England and Wales and from 8.8 to 2.2% in the United States. Hallucinogens are less harmful than most licit and illicit drugs, and recent observational, experimental, and clinical studies suggest that these compounds have antidepressive, anxiolytic, and antiaddictive effects, especially in treatment-resistant patients.

Although many studies have been conducted on the effects of serotonergic hallucinogens on perceptions, emotions, and cognition, the neural basis of these effects is still poorly understood. Therefore, we conducted a systematic review of human studies applying neuroimaging techniques to analyze the effects of serotonergic hallucinogens.

Studies are available for some hallucinogenic drugs, but meta-analysis has inherent limitations. Therefore, a meta-analysis is not appropriate.

Ayahuasca, DMT, psilocybin, LSD, mescaline, and mri were searched in the SciELO databases. All studies published until 12 April 2016 were included.

After inspection for duplicates, the titles and abstracts of all records were reviewed. Publications that clearly did not meet inclusion criteria were excluded, and a third reviewer included if consensus could not be reached.

278 references were reviewed for title and abstract screening, and 25 potentially relevant references were identified. Two citations were excluded because they presented preliminary data or neuroimaging results already reported, and two citations were found after hand search of the bibliography of the selected reports.

The results of 23/25 studies using acute drug administration (open-label, single- or double-blind placebo-controlled studies) and 2 retrospective, observational studies (Erritzoe et al., 2011; Bouso et al., 2015) show that serotonergic hallucinogens modulate neural networks implicated in visual information processing and cognitive functions and emotional processing.

Mescaline increased regional cerebral blood flow in frontal cortical regions, and decreased activity in posterior cortical regions, but had no effect on subcortical areas or the performance of the face test.

In Germany, Daumann et al. (2008) and Daumann et al. (2010) performed a randomized, double-blind, cross-over, placebo-controlled, BOLD fMRI study on volunteers using DMT and S-ketamine to assess the neural correlates of the mental states induced by DMT and S-ketamine.

DMT and S-ketamine reduced BOLD activity in extrastriate regions during visual alerting and increased cortical activation in the left insula and precentral gyrus during the auditory modality, with visual effects being more pronounced. Psilocybin increased CMRglu in the frontomedial and frontolateral cortex, anterior cingulate, temporomedial cortex, and putamen.

Psilocybin decreased 11 C-raclopride receptor binding potential in the striatum of seven healthy male volunteers, suggesting an increased D2-dopamine receptor occupancy by endogenous dopamine. In Germany, Gouzoulis-Mayfrank et al. (1999) performed a PET study with 32 healthy volunteers and administered psilocybin, MDE and d-methamphetamine. Psilocybin increased rMRGlu in the right anterior cingulate and in the right frontal operculum compared with placebo, and decreased rMRGlu in the right thalamus and in the left precentral region. MDE and d-methamphetamine induced rMRGlu increases in the cerebellum and reductions in the cortical rMRGlu in the composite bilateral entire region.

A single-blind, within-subjects, counterbalanced-order, placebo-controlled study performed in the United Kingdom found that intravenously administered psilocybin decreased rCBF in several brain regions and had a positive correlation with the intensity of the subjective effects induced by psilocybin. Following this initial study, several re-analyses of the fMRI data from the original sample were published, showing that psilocybin induced significant increases in ratings of memory vividness and imagery, and a significant positive correlation between vividness and subjective wellbeing.

In a re-analysis of fMRI data, psilocybin increased functional connectivity between the default-mode network and the salience network, right frontoparietal network, and auditory network, but not with the thalamocortical network. Psilocybin administration increased the variability of BOLD signal variance and total spectral power in the anterior cingulate cortex and bilateral hippocampi, and decreased the low frequency power and frequency scaling exponent in the frontal and parietal regions corresponding to higher-level association regions such as the DMN, executive control, and dorsal attention networks.

Psilocybin increased coupling in the following resting-state networks: Visual – Medial Network/left Frontoparietal Network, Visual – Medial Network/Dorsal Attention Network 1.

The visual, auditory, executive control, frontoparietal, occipital pole, and sensorimotor networks are involved in visual and auditory processing.

Psilocybin and MDMA had different effects on resting-state functional connectivity and subjective effects, suggesting that psilocybin has more profound effects on global brain function.

In a double-blind, randomized, cross-over, placebo-controlled study performed in Switzerland, psilocybin significantly decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex compared with placebo.

A re-analysis of the fMRI data from Carhart-Harris et al. (2012) found that psilocybin-induced “ego-dissolution” was associated with decreased diversity of the anterior parahippocampal connections, decreased integrity of the salience network, and reduced interhemispheric communication.

LSD significantly increased the number of words in mentation reports and induced fewer mental spaces for the past compared with placebo. There was no significant correlation between LSD and present or future mental spaces, however, a correlation between LSD and greater decreases in DMN resting-state functional connectivity almost reached statistical significance.

LSD significantly increased resting-state functional connectivity in the primary visual cortex and several cortical and subcortical brain regions, and decreased resting-state functional connectivity in the parahippocampal region and the retrosplenial cortex/posterior cingulate cortex. This decreased functional connectivity was correlated with subjective ratings of “ego-dissolution” and “altered meaning”.

LSD increased global functional connectivity in high-level association cortices, and also increased communication between association and sensory cortices. These increases were positively correlated with subjective ratings of “ego dissolution” and increased global functional connectivity in high-level association cortices after psilocybin administration. Using fMRI, Kaelen et al. (2016) investigated the interaction between parahippocampal cortex functional connectivity and LSD and music during an eyes-closed mental imagery task. They found that the interaction was associated with increased parahippocampal cortex to visual cortex information flow.

A single oral dose of encapsulated freeze-dried ayahuasca mg DMT/kg] induced significant activation of the anterior insula/inferior frontal gyrus, the frontomedial wall of the right hemisphere, and the amygdala/parahippocampal gyrus in 15 healthy male volunteers.

In an open-label study in Brazil, de Araujo et al. (2012) found that ayahuasca increased activation in the precuneus, cuneus, lingual, fusiform, middle occipital, parahippocampal, posterior cingulate, superior temporal, superior middle, and inferior frontal gyri during an imagery task.

Ayahuasca significantly decreased activation of key hubs of the default mode network (DMN) during a verbal fluency task, and also decreased functional connectivity within the posterior cingulate cortex/precuneus.

Ayahuasca administration to 17 volunteers with Depressive Disorder increased blood perfusion in the left nucleus accum-right insula, and left subgenual area, and reduced days after drug intake.

A group of 24 users of MDMA and/or hallucinogenic drugs were compared to 21 nonusing controls using PET. They found that MDMA users had significant reductions in serotonin transporter and 5-HT2A receptor binding compared with hallucinogen users and controls in the pallidostriatum, amygdala, and neocortex.

Users had slightly lower neocortical 5-HT2A receptor binding than controls, with regional decreases of in the neocortex. However, when two controls with very high 5-HT2A receptor binding values were excluded from the sample, the difference between users and nonusers was no longer statistically significant. In an observational, retrospective study performed in Spain, Bouso et al. (2015) found that regular ayahuasca use was significantly associated with cortical thinning in the mesotemporal and inferior frontal gyri, precuneus, superior frontal gyrus, posterior cingulate cortex and superior occipital gyrus, but no evidence of increased psychopathology.

Serotonergic hallucinogens induce excitatory effects in the frontolateral/frontomedial cortex, medial temporal lobe, amygdala, in different laboratories and using different technics. However, resting-state fMRI studies showed significant reductions in brain activation in the same regions where neurochemical imaging studies showed increased activation. PET/SPECT results could be inconsistent with fMRI results because the radiotracers used to measure blood perfusion/glucose metabolism have long half-lives and use greater time-scales than fMRI measures. Studies using fMRI showed that psilocybin, ayahuasca, and a cuneus and lingual gyrus significantly activated the primary visual area, and that psilocybin significantly attenuated right amygdala activation to both negative and neutral pictures. The interpretation of functional connectivity results is even more difficult, as several studies reported increased coupling between cortical networks, suggesting an increased integration between cortical regions. Furthermore, structural MRI studies reported significant cortical thinning in mesotemporal and inferior frontal gyri and posterior cingulate cortex.

Researchers found no effects on serotonergic hallucinogen SERT values and slight reduction on 5-HT2A receptor densities, but significant effects on 5-HT2A receptor densities were observed only when both group of MDMA/hallucinogens users were analyzed together.

Ayahuasca administration to rats was associated with decreased concentrations of glycine and -aminobutyric acid in the amygdala, increased GABA levels in the hippocampus, and an increased utilization rate of noradrenaline, dopamine, and serotonin in the amygdala. A recent study showed that psilocin increased MRI signal in the hypothalamus, olfactory regions, amygdala, and other limbic regions, and also increased cerebral blood flow in the somatosensory cortex after sensorial stimuli. However, MRI signal decreases were observed in the cingulate, motor, and somatosensory cortices. Neurophysiological studies in humans using electroencephalography and MEG consistently show that serotonergic hallucinogens decrease the power of lower frequency oscillations in key regions of the DMN, which induces an excitotatory effect. These effects create a state of “expanded awareness”, “ego-dissolution”, and “unconstrained cognition”. Agonists at frontocortical 5-HT2A receptors modulate glutamatergic neurotransmission and increase the expression of neurotrophic factors, thereby enhancing neuroplasticity and neurogenesis. Preclinical and human research suggests that ayahuasca, psilocybin, and LSD have antidepressive, anxiolytic, and antiaddictive properties. Moreover, psychological mechanisms may also play a role in the therapeutic properties of these drugs, and appear to be related to neuroimaging findings.

Serotonergic hallucinogens appear to be related to their ability to elicit religious/mystical experiences, and this is supported by the decreased DMN activity and decreased DMN-TPN inverse coupling observed not only after administration of serotonergic hallucinogens, but also in meditation.

The effects of serotonergic hallucinogens include acute increases in blood perfusion/glucose metabolism in prefrontal and limbic areas involved in the regulation of mood, interoception, cognition, and consciousness, decreases in reactivity of brain structures related to anxiety/fear processing, and reduced brain activity in key regions of the DMN, involved in mind-wandering and self-awareness.

Serotonergic hallucinogens may improve our understanding of psychiatric disorders, consciousness, and other complex topics, and may also have thera- peutic effects. Further development of neuroimaging techniques, better sample and drug delivery standardizations, and the integration of data across neuroimaging modalities are needed.