LSD: Precision Neuroimaging of Neural Responses

In healthy, hallucinogen-experienced volunteers.

Overview

  • This will be an exploratory study investigating the neural responses to LSD using fMRI and MEG

  • The Beckley Foundation have awarded ~£150,000

  • The study will be sponsored by King’s, where the drug will be stored

  • Imaging at high resolution (7 Tesla) at the WCHN (UCL)

  • Scanning healthy, experienced volunteers prior, during and after dosing with LSD

  • Volunteers will have two scanning days with drug dosing and two scanning days without any drug

  • Blood samples will also be collected and preserved to eventually study the epigenetic effects of LSD

Collaborators

  • Amanda Fielding

  • Rob Leech

  • Rosalyn Moran

  • Karl Friston

  • Anjali Bhat

  • Valerie Bonnelle

  • Rick Adams

  • Prateek Yadav (Teek)

  • Federico Tukheimer (FET)

  • Leor Roseman

  • Joost Haarsma

  • Deepak Srivastava

Background

Pharmacology:

  • First synthesised from ergot (grain mould that causes vascular and muscular constriction – ‘St Anthony’s Fire’)

  • Structurally similar to serotonin (5-HT), influences brain activity by binding with 5-HTR2A receptors

  • Binds with 5-HTRs with greater affinity than serotonin itself, leading to enduring effects


Phenomenology:

  • An LSD trip lasts 8-12 hours

  • Heightened sensations; enhanced introspection and suggestibility; hallucinations; feelings of joy, peace and sacredness; synaesthesia; elevated blood pressure and muscle tension; transcendence of time/space; ‘revelations’ or insights that can engender enduring alteration of core beliefs

  • Set and setting strongly influence the experience

  • However, there is significant individual variability:

“In spite of a good mood at the beginning of a session—positive expectations, beautiful surroundings, and sympathetic company—I once fell into a terrible depression. The unpredictability of effects is the major danger of LSD.” - Albert Hoffman

Aims and Impact

  • Inform the neurobiology of consciousness

  • Improve our understanding of why LSD appears to help patients with addiction, PTSD, terminal illness

  • Give us insights into how it may affect patients with other major mental/neurological disorders (personality disorders, psychosis, Alzheimer’s disease)

  • Mitigate risks of inevitable recreational use


We, therefore, aim to:

  • Take an individualised approach (i.e., a case series), in which the intertwining influences within subjects are thoroughly characterised (group-level analyses do not afford the same level of nuance)

  • Produce a rich and well-characterised resource of behavioural, MEG, task fMRI (7T), structural MRI, experience sampling and genetic/epigenetic data, which will eventually be made open source

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Novelty

This will build on past fMRI studies of responses to psychedelics by:

  • Using high-resolution (7 Tesla) laminar imaging, which will allow us to look at individual cortical layers

  • Two dosing sessions

  • Within-subjects/case series (prior psychedelic studies have analysed group averages)

  • Experience sampling throughout (structured in the first dosing session and open-ended in the second)

  • Subjects choose their dose in the second session

  • Transcriptomics conducted on blood samples from participants

  • Task fMRI (not just resting-state)

  • Effective connectivity (layer-specific dynamic causal modelling, DCM)

  • Influences on blood flow (vascular DCM & regional aerobic glycolysis)

  • Focusing on LSD: due to trip length, neural responses under LSD are not as well-characterized as under psilocybin

Hypotheses

This is an exploratory so not all hypotheses are pre-defined, but here are some potential questions:

  • Cortical organisation: imaging at a higher resolution also allows for investigating mechanisms of top-down vs bottom-up information flow across regions and layers of the cortex under psychedelics that have been hypothesised previously (Carhart-Harris & Friston) but so far have not been possible to test empirically.

  • Longitudinal: are there any enduring changes in brain structure several weeks after having taken LSD?

  • Experiential: does neural ‘entropy’ (LZ complexity, MEG resting state) increase with peak experience/ego-dissolution?

  • Sensory: does LSD reduce mismatch negativity like ketamine does, or like in psychosis?

  • Vascular: Is there significant constriction of blood vessels in the brain under LSD? Does this correspond to ego loss?

  • Energetic: Does regional aerobic glycolysis indicate a return to a more ‘youthful’ neural state under LSD?

  • Epigenetic: characteristic changes in gene expression and DNA methylation 1 day after and 1 week after taking LSD