Abstract by Drummond McCulloch

Psychedelic drugs, including LSD and psilocybin, produce a wide range of scientifi cally intriguing acute and persisting behavioural eff ects. These include transient mystical, meaningful, and ineff able experiences as well as lasting reductions in symptom severity across a range of psychiatric disorders or increases in wellbeing in healthy individuals. The present PhD thesis seeks to develop our understanding of the neurological underpinnings of these acute and lasting eff ects using functional magnetic resonance imaging (fMRI) and Positron Emission Tomography (PET), and by evaluating the relation between the acute mystical-type eff ects and persisting eff ects in healthy people.
Paper 1 evaluated the persisting eff ects of a single dose of psilocybin on fMRI-derived brain-network connectivity in healthy individuals. Paper 2 evaluated the relation between psilocybin induced mystical-type experiences, measured using the Mystical Experiences Questionnaire (MEQ), and persisting positive eff ects in healthy people and provided a qualitative description of these mystical-type experiences. Paper 3 built on previous hypothesis-generating research that suggested psychedelics increase fMRI-measured brain-entropy, testing these hypotheses in an independent and larger cohort and presenting a toolbox resource for future researchers. Paper 4 evaluated the relation between plasma LSD levels, acute subjective eff ects, functional brain eff ects using fMRI, and occupancy at the serotonin 2A receptor (5-HT2AR) using [11C]Cimbi-36 PET.
Paper 1 showed a network-wide decrease in functional connectivity in the executive control network, which was associated with increases in self-reported mindful-attention and awareness, highlighting a potential neural mechanism through which psilocybin may have its persisting behavioural eff ects. Paper 2 found that the subscales mystical and positive mood of the MEQ were signifi cantly related to persisting positive eff ects, but that the subscales ineff ability and transcendence of time and space were not. Natural-language processing revealed themes exclusive to mystical-type experiences, such as feelings of unity with the universe, familial love, and profound aesthetic experiences. Paper 3 identifi ed that previously reported measures of fMRI brain entropy were distinct and uncorrelated. Despite this, three of the thirteen metrics evaluated were signifi cantly correlated with acute psychedelic eff ects and are thus candidate biomarkers for acute neural eff ects of psychedelics. These included increases in the distribution of connectivity paths across the brain, the distribution of connectivity strengths over time, and the unpredictability of the signal across several brain areas. Paper 4 showed a close relation between plasma LSD levels and occupancy at the 5-HT2AR, which can inform future dosing strategies. fMRI analyses showed decreases in the global connectivity of the cortex, which was correlated with 5-HT2AR occupancy.
In conclusion, the present work constitutes a wide knowledge base describing the acute and lasting eff ects of psychedelics both behaviourally and neurologically. These fi ndings can be used to design future studies, highlighting candidate biomarkers that can be used to develop our understanding of altered states of consciousness. These data show that measuring psychedelic eff ects using plasma drug level measurements and behavioural questionnaires in combination with fMRI and PET imaging can assist in our understanding of the brain and the eventual development of future therapeutics.