Neuroimaging in psychedelic drug development: past, present, and future

Abstract

Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. ‘Classic’ serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a ‘molecular-functional-clinical bridge’ in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.

A rapid narrative review of the clinical evolution of psychedelic treatment in clinical trials

“…Further, during the pre-prohibition era, the effects of psychedelics were primarily characterized in terms of psychological changes, especially with respect to the dramatic alterations in consciousness. Today, with advancements in neuroimaging and molecular biology, we have modern tools that can aid in understanding the neurobiological alterations in the nervous system underlying the observed psychological phenomena 80 , 81 . Correspondingly, this may support the development of a more comprehensive, biopsychosocial understanding of mental ill health and approach to psychedelic treatment, enabling the identification of biomarkers informing patient suitability for treatment and predictors of response to inform precision treatment planning.…”

Psychiatric Neuroimaging Designs for Individualised, Cohort, and Population Studies

“…Cohort designs have been widely used, with varying success, to investigate circuit-level "mechanisms of action" underlying psychiatric treatments such as TMS [40], deep brain stimulation (DBS; [41]) and pharmacological intervention [42]. Cohort designs have likewise been invaluable for characterising average changes in normative brain development during the lifespan period of adolescence when psychiatric disorders first emerge [43][44][45][46][47].…”

Psychedelics in developmental stuttering to modulate brain functioning: a new therapeutic perspective?

“…In this context, more work is needed to understand how the increased neural plasticity induced by psychedelics (see Calder and Hasler, 2023 ) is linked to the changes in brain circuitry and increase in “entropy” of neural networks ( Carhart-Harris and Friston, 2019 ; Inserra et al, 2021a ; Herzog et al, 2023 ; Ort et al, 2023 ; Wall et al, 2023 ). The “acute” and “rebound” activity could be in opposite directions when considering brain metabolism (see Vollenweider et al, 1997 ; Carhart-Harris et al, 2012 ).…”

“…Moreover, psychedelics seem to “disrupt” connectivity, especially in resting-state networks such as the DMN, also resulting in induced modifications of the functional connectivity between these circuits and other brain networks ( Carhart-Harris et al, 2013 , 2017 ; Daws et al, 2022 ; Felsch and Kuypers, 2022 ) that, for example, may favor “goal-directed” behaviors. In this context, a series of different models have been proposed that attempt to explain the various effects of doses of psychedelic drugs on the brain, also making assumptions about their induced neural modulations (e.g., DMN; Carhart-Harris and Friston, 2019 ; Vollenweider and Preller, 2020 ; Daws et al, 2022 ; Doss et al, 2022 ; Gattuso et al, 2023 ; Herzog et al, 2023 ; Wall et al, 2023 ). Nonetheless, it is still not clear what is the main brain target of the therapeutic potential of, for example, psilocybin ( Gattuso et al, 2023 ).…”