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

Abstract

Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating a range of psychiatric disorders, including depression, addiction, eating disorders, post-traumatic stress disorder, and others. ‘Classic’ serotonergic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), N, N-Dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), form the main focus of this movement, but other substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The development of these novel treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This has enabled assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline some of the major trends in existing data and suggest that the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified which can be addressed by future neuroimaging work, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Suggestions for future multimodal imaging studies are discussed, which would resolve some of these questions and provide a firmer foundation for the development of PT.

Use of psychedelic treatments in psychiatric clinical practice: an EPA policy paper

“…For terminally ill patients experiencing existential distress, psychedelics show promise based on a systematic review of 33 studies [11). Few studies address PTSD and classic psychedelics, but ongoing open-label trials with psilocybin and ayahuasca show promising results [ 12 , 13 ]. A larger body of research including Phase 2 and Phase 3 trials with MDMA-assisted therapy in PTSD has been published over the last two decades, but this is outside the scope of this paper given our focus on traditional psychedelics [ 14 ].…”

“…Within the scope of this policy paper, a full overview of all research findings is not possible. For a more in-depth understanding, we refer to the many, excellent available reviews (e.g., [ 11 , 12 ]).…”

Use of psychedelic treatments in psychiatric clinical practice: an EPA policy paper

“…For terminally ill patients experiencing existential distress, psychedelics show promise based on a systematic review of 33 studies [11). Few studies address PTSD and classic psychedelics, but ongoing open-label trials with psilocybin and ayahuasca show promising results [ 12 , 13 ]. A larger body of research including Phase 2 and Phase 3 trials with MDMA-assisted therapy in PTSD has been published over the last two decades, but this is outside the scope of this paper given our focus on traditional psychedelics [ 14 ].…”

“…Within the scope of this policy paper, a full overview of all research findings is not possible. For a more in-depth understanding, we refer to the many, excellent available reviews (e.g., [ 11 , 12 ]).…”

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, 2017Daws et al, 2022;Felsch and Kuypers, 2022) that, for example, may favor "goaldirected" 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 10.3389/fnhum.2024.1402549 (Gattuso et al, 2023).…”

Neuroimaging and the Investigation of Drug-Drug Interactions Involving Psychedelics

“…Wall et al 9 recently outlined the role that neuroimaging has played in the modern development of these pharmacotherapy approaches. Functional Magnetic Resonance Imaging (fMRI) studies have formed a crucial part of mechanistic-focused studies with healthy 10,11 and clinical populations.…”

Use of psychedelic treatments in psychiatric clinical practice: an EPA policy paper

“…For terminally ill patients experiencing existential distress, psychedelics show promise based on a systematic review of 33 studies [11). Few studies address PTSD and classic psychedelics, but ongoing open-label trials with psilocybin and ayahuasca show promising results [ 12 , 13 ]. A larger body of research including Phase 2 and Phase 3 trials with MDMA-assisted therapy in PTSD has been published over the last two decades, but this is outside the scope of this paper given our focus on traditional psychedelics [ 14 ].…”

“…Within the scope of this policy paper, a full overview of all research findings is not possible. For a more in-depth understanding, we refer to the many, excellent available reviews (e.g., [ 11 , 12 ]).…”

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, 2017Daws et al, 2022;Felsch and Kuypers, 2022) that, for example, may favor "goaldirected" 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 10.3389/fnhum.2024.1402549 (Gattuso et al, 2023).…”

Neuroimaging and the Investigation of Drug-Drug Interactions Involving Psychedelics

“…Wall et al 9 recently outlined the role that neuroimaging has played in the modern development of these pharmacotherapy approaches. Functional Magnetic Resonance Imaging (fMRI) studies have formed a crucial part of mechanistic-focused studies with healthy 10,11 and clinical populations.…”

Use of psychedelic treatments in psychiatric clinical practice: an EPA policy paper

“…For terminally ill patients experiencing existential distress, psychedelics show promise based on a systematic review of 33 studies [11). Few studies address PTSD and classic psychedelics, but ongoing open-label trials with psilocybin and ayahuasca show promising results [ 12 , 13 ]. A larger body of research including Phase 2 and Phase 3 trials with MDMA-assisted therapy in PTSD has been published over the last two decades, but this is outside the scope of this paper given our focus on traditional psychedelics [ 14 ].…”

“…Within the scope of this policy paper, a full overview of all research findings is not possible. For a more in-depth understanding, we refer to the many, excellent available reviews (e.g., [ 11 , 12 ]).…”

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, 2017Daws et al, 2022;Felsch and Kuypers, 2022) that, for example, may favor "goaldirected" 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 10.3389/fnhum.2024.1402549 (Gattuso et al, 2023).…”

Neuroimaging and the Investigation of Drug-Drug Interactions Involving Psychedelics

“…Wall et al 9 recently outlined the role that neuroimaging has played in the modern development of these pharmacotherapy approaches. Functional Magnetic Resonance Imaging (fMRI) studies have formed a crucial part of mechanistic-focused studies with healthy 10,11 and clinical populations.…”