Psychedelic Therapy’s Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

This review (2021) uses the Research Domain Criteria (RDoC) as a template to analyse the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, covering molecular, cellular and network levels. This is the first review to use the RDoC to explore psychedelic therapies and may facilitate a precise-personalized psychedelic therapy paradigm.


“Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.”

Authors: John R. Kelly, Claire M. Gillan, Jack Prenderville, Clare Kelly, Andrew Harkin, Gerard Clarke & Veronica O’Keane


Crises induce a wide range of psychological reactions, with varying degrees of adaptability. The COVID-19 pandemic may cause increased psychological and psychiatric problems, with an excess burden on vulnerable groups.

Psilocybin therapy may be effective in the treatment of depression, obsessive compulsive disorder and addiction disorders, and there may be a role for psilocybin therapy in the treatment of anxiety disorders.

Recent advances in psychedelic science are gradually unravelling the multimodal mechanisms underlying the therapeutic effect of psilocybin therapy. Psilocybin alters an individual’s state of consciousness, probably through agonist mechanisms at the 5-HT2A receptor, especially in the deep pyramidal cells in the cortex.

Psilocybin therapy provides a translatable, transdiagnostic treatment strategy that can be further refined by a precise-personalised approach. Moreover, a dimensional framework that aligns with bio-psycho signatures may also be leveraged to enhance the targeted application of psilocybin therapy.

Despite limitations, preclinical data suggest that serotonergic psychedelics, including psilocybin, can induce hippocampal neurogenesis, promote dendritic spine growth and stimulate synapse formation in the prefrontal cortex.

Researchers from Johns Hopkins University studied the claustrum, a thin sheet of grey matter embedded in the white matter of the cerebral hemispheres, and found that psilocybin altered activity and connectivity in this region.

In an open-label pilot study, 12 healthy volunteers showed reduced negative affect and amygdala responses to emotional stimuli, whereas in a larger study, 19 subjects with treatment-resistant depression showed increased amygdala responses and decreased functional connectivity.

In the midst of the ‘Psychedelic Revolution in Psychiatry’ and potential increasing recreational psychedelic use, the Royal Australian and New Zealand College of Psychiatrists published a clinical memorandum on the therapeutic use of psychedelic substances.

Results from the Global Drug Survey (2019) showed that only 18% of people who have never used psychedelics would accept psilocybin therapy for depression or PTSD, and that 59% of people who had previously tried psychedelics would accept it. However, high-quality clinical data is lacking.

HPPD may be caused by arousal-altering drugs, including non-hallucinogenic substances. However, regular psychedelic use may have a limited impact on the brain.

Dublin is one of the clinical trial centres participating in a double-blind randomised controlled phase 2b COMPASS trial of psilocybin therapy in treatment-resistant depression. The trial will address concerns regarding psilocybin safety, efficacy and dose optimisation, and will also examine the effects of psilocybin therapy in conjunction with SSRIs.

A new study will be launched in Dublin and San Diego to determine the antidepressant effect of psilocybin therapy in people with TRD who continue SSRI medication. The results of this study may have important practical implications for the future of psilocybin therapy.

Clinical and research psychiatry have been transformed by COVID-19, and additional strategies are needed to overcome the considerable challenges. These include respiratory symptom checklists, regular temperature checks, access to COVID-19 testing, and meticulous attention to extra hygiene measures.

Study details

Topics studied

Study characteristics

0 Humans

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