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.

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).…”

Psychedelic therapy in the treatment of addiction: the past, present and future

“…A placebo-controlled study of psychedelic-naive healthy individuals given ayahuasca revealed increased ACC connectivity within the SN, decreased PCC connectivity within the DMN and increased connectivity between the SN and DMN 1 day after ayahuasca ( 131 ). Intriguingly, increased global coupling and functional connectivity between SN and DMN nodes have been found under acute psilocybin administration ( 141 ) but future work, ideally combining multimodal molecular and functional neuroimaging ( 142 ), is needed to elucidate how mid- and long-term functional interactions of both networks are changed by psychedelic therapy in populations with addiction and how these relate to prognosis.…”

“…Each of these methods have provided varying levels of detail on the nuances of molecular dysfunction in addiction and hence could be used as a proxy to explore how such parameters may predict response to psychedelic therapies and if psychedelic therapies restore any of the observed molecular deficits. More recently, human molecular neuroimaging has offered insight into the neurochemical mechanism(s) of action of psychedelics although to a much less extent than fMRI ( 142 ).…”

“…This mechanism is theorized to be effective across a range of psychopathologies characterized by ‘canalisation’ [for a thorough review please see: ( 173 , 174 )]. In brief, the assessment of neuroplasticity can focus on changes at a cellular and molecular level using PET ligands focusing on several proteins including; synaptic glycoprotein 2A (SV2A, a marker of pre243 synaptic terminals; [ 11 C] UCB-J) and mitochondrial complex 1 (MC1, a marker of mitochondrial density; [ 18 F]BCPP-EF) offer promising prospects ( 142 ). These techniques could investigate pathological biomarkers of plasticity with evidence for reduced SV2A in the PFC in CUD ( 175 ).…”