Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

This double-blind, placebo-controlled study (n=58) investigated the effect of two doses of psilocybin (11mg-15mg/70kg) on cerebral blood flow. The larger dose led to significantly higher ratings on 4 of 11 scales of altered consciousness. It also showed which specific brain regions became more, and less, active.

Abstract

“Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. We controlled for sex and age and used family-wise error corrected p values in all neuroimaging analyses. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations.”

Authors: Candace R. Lewis, Katrin H. Preller, Rainer Kraehenmann, Lars Michels, Philipp Staempfli & Franz X. Vollenweider

Summary

Psilocybin, the active compound in psychedelic mushrooms, increases glucose metabolism in frontal cortex and decreases perfusion in other brain regions. This study used pseudo-continuous arterial spin labeling to measure perfusion changes in two groups of healthy controls after two doses of oral psilocybin.

Recent research suggests that moderate doses of psilocybin enhance positive mood and attenuate the BOLD response to negative stimuli in healthy participants, and may be related to the long-term antidepressant or anxiolytic effects reported in earlier and recent studies with psilocybin or LSD.

Neuroimaging studies of psilocybin and other 5-HT modulators have found contradictory results that necessitate clarification. These studies measured different physiological properties and should not be directly compared, however, the neuronal processes are coupled, thus further investigation is necessary.

Quantitative neuroimaging techniques can be used to measure local changes in neural activity in response to a pharmacological challenge. However, the effects of psilocybin on vascular tone need to be accounted for by a normalization procedure in the analysis.

We investigated two doses of oral psilocybin administration using pseudo continuous arterial spin labeling (pCASL) fMRI and predicted that psilocybin would induce a similar hypermetabolic frontal rCBF pattern observed in glucose metabolism PET studies.

1.1. Participants

Participants were recruited through advertisements in local universities and received either a low dose of 0.16 mg/kg or a high dose of 0.215 mg/kg.

We chose a low medium dose and a high medium dose for this first neuroimaging dose comparison study. All participants provided written informed-consent statements in accordance with the declaration of Helsinki before participation in the study.

1.2. Experimental design and drug administration

In a randomized, double blind, and placebo-controlled study, participants received either Placebo (maltose) or oral psilocybin in two separate sessions at least 10 days apart.

1.4. Statistical analysis

The 5D-ASC comprises 94 items to be answered on visual analogue scales, and 11 validated scales were calculated. A repeated-measures ANOVA was conducted with two within-subject factors of drug and scale.

We performed a group-level analysis of the ASL images using a general linear model implemented in SPM12. We also performed a t-test to assess the relationship between psilocybin and rCBF, and used a normalization ANOVA option and a whole brain AAL mask to calculate mean CBF values.

procedure

After normalization, the pCASL SPM map revealed significant local drug effects in the following areas: bilateral inferior frontal gyrus and insula, right side hippocampus, operculum, and temporal superior gyrus.

3. Discussion

We controlled for the global signal in order to localize unique relative effects and found psilocybin induces both increases and decreases in rCBF, mirroring results from previous PET studies. We also found psilocybin reduces gCBF when compared to placebo, but the mechanism is too subtle to be captured by ASL data.

Our analysis, which controls for global variance, aligns well with the seminal psilocybin investigations using PET, which demonstrated general hyperfrontal effects. We also found decreases in rCBF in the thalamus, which partially overlaps with the activation pattern seen in PET studies corrected for global variance.

Using resting-state pharmacological ASL designs, we can measure unique regional effects likely driven by drug action on local receptors. Especially interesting, we found that psilocybin induces a more robust right laterality in metabolic hyperfrontality despite higher 5-HT2A receptor expression rates in left frontal, cingulate, and orbital cortex.

The High dose of psilocybin produced significantly stronger alterations on four of the 11 scales compared to Low dose psilocybin, but the High dose group did not report elevated levels of anxiety compared to the Low dose group.

Drugs induce changes in cerebral blood flow via multiple mechanisms, including local vasodilation and constriction via inhibitory interneuron direct actions on smooth muscle, local excitatory neurons, and global pathways involving serotonin. Psilocybin decreases gCBF, which is likely due to its effect on general vascular tone. However, psilocybin effects on neuronal glucose metabolism also affect rCBF, which may be due to regional differences in brain microvasculature.

In phMRI ASL resting state investigations, it is common practice to report both analyses with and without a global covariate, but not all reports clearly state if a global covariate was used, leaving the reader to assume no global signal was regressed out.

Our study has limitations, such as the between-subjects dose comparison, but the two groups were well matched for age and sex. Furthermore, the routs of administration differed between studies, which may account for the discrepancy in the literature concerning psilocybin effects on CBF. Psilocybin action in brain regions associated with psychiatric disorders is important to understand, and CBF in relation to global signal variations is a vital contribution to the existing literature.