Towards mapping neuro-behavioral heterogeneity of psychedelic neurobiology in humans

Flora Moujaes, Katrin H. Preller, Jie Lisa Ji, John D. Murray, Lucie Berkovitch, Franz X. Vollenweider, Alan Anticevic

Biological Psychiatry, 2023

doi : 10.1016/j.biopsych.2022.10.021

ABSTRACT

Precision psychiatry aims to identify markers of inter-individual variability that allow predicting the right treatment for each patient. However, bridging the gap between molecular-level manipulations and neural systems-level functional alterations remains an unsolved problem in psychiatry. After decades of low success rates in pharmaceutical R&D for psychiatric drugs, multiple studies now point to the potential of psychedelics as a promising fast-acting and long-lasting treatment for some psychiatric symptoms. Yet, given the highly psychoactive nature of these substances, a precision medicine approach is essential to map the neural signals related to clinical efficacy in order to identify patients who can maximally benefit from this treatment. Recent studies have shown that bridging the gap between pharmacology, systems-level neural response in humans and individual experience is possible for psychedelic substances, therefore paving the way for a precision neuropsychiatric therapeutic development. Specifically, it has been shown that the integration of brain-wide PET or transcriptomic data, i.e. receptor distribution for the serotonin 2A receptor, with computational neuroimaging methods can simulate the effect of psychedelics on the human brain. These novel ‘computational psychiatry’ approaches allow for modeling inter-individual differences in neural as well as subjective effects of psychedelic substances. Collectively, this review provides a deep dive into psychedelic pharmaco-neuroimaging studies with a core focus on how recent computational psychiatry advances in biophysically based circuit modeling can be leveraged to predict individual responses. Finally, we emphasize the importance of human pharmacological neuroimaging for the continued precision therapeutic development of psychedelics.

INTRODUCTION

Classic psychedelics are substances that acutely induce an altered state of consciousness and act primarily as partial or full agonists on the serotonin 2A (5-HT2A) receptor localized on apical dendrites of Layers IV-V pyramidal neurons (1–3). In western medicine, psychedelics were first investigated for their “psychotomimetic” effects : they were used to experimentally induce a temporary state of consciousness mimicking certain aspects of mental illnesses, in particular psychosis (4). This line of research has greatly advanced our understanding of the neurobiological and neuropharmacological basis of psychiatric disorders and continues to reveal important insights for drug development (4). The discovery of the psychoactive effects of LSD in 1943 then catalyzed the second branch of psychedelic research testing these molecules in the treatment of psychiatric disorders (5). While these early clinical trials often suffer from methodological limitations, their results point to clinical efficacy across multiple indications (6).

Psychedelics are being investigated in humans after a hiatus of several decades, which was caused by the decision to place these substances in Schedule I in 1970 in the US and subsequently many other western countries (7). Although more data is needed and critical questions regarding dose and administration frequency still need to be answered, an increasing number of modern studies show promising safety, tolerability, and efficacy data in various patient populations (8–13). This has given rise to the therapeutic framework “psychedelic-assisted therapy”. In these studies, psilocybin, LSD, and ayahuasca provide fast-acting and long-lasting symptom relief after only one or two administrations when embedded in a psychotherapeutic program. However, the acute and delayed neural mechanisms conferring this effect remain largely unknown.

The rapid growth of neuroimaging technology has greatly advanced our understanding of psychedelics’ acute system-level effects and the concurrent changes in behavior (7). However, given the highly psychoactive nature of these substances, a precision approach is badly needed to identify person-specific neural and behavioral responses and in turn patients who can maximally benefit. To achieve personalized precision, the key knowledge gap involves mapping within- and between-individual neuro-behavioral variation of acute and long-term psychedelic effects to pinpoint the neural targets that reflect specific symptom changes in clinical populations.

To advance psychedelic-assisted precision therapy, this review provides a deep dive into psychedelic pharmacological neuroimaging studies. We focus on recent advances in computational psychiatry and neuroimaging analytics that can inform neural system level targets for predicting personalized response patterns. We aim to provide an integrative view of how to move the field toward precision pharmaco-fMRI for iterative and rational refinement of psychedelic-assisted therapy as a viable tool in psychiatry. We describe the limitations of currently available datasets and provide a strategic roadmap for future study design and analysis that can close current knowledge gaps.

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