Psychopharmacology of psychedelics

In the last few years there has been a surge in interest in the potential clinical benefits of psychedelic drugs. This has also led to new investment not only to study the clinical effects of these drugs but also to better understand their fundamental biology. Through this work, new treatments with better tolerability and wider clinical applications may be developed. It is somewhat surprising to find that our knowledge of the fundamental biology of psychedelic drugs remains so limited. Although psychedelic effects of drugs have been exploited by humans for millennia and utilised in psychiatry up until the 1970s, much about the underlying mechanisms remains unknown. Many are naturally occurring substances with complex pharmacology and interact with many different receptor populations. Not all psychedelics are the same and even small differences in their pharmacology may have big impacts on their behavioural effects. For example, most of the serotonergic psychedelics have activity at the 5-HT2A receptor but also act at other 5-HT receptors and it is still not known which receptors or combination of receptors contribute to the different aspects of their effects. We also now know that drugs with very different primary targets at a molecular level e.g. the NMDA receptor antagonist ketamine and muscarinic antagonist, scopolamine, share a common neuropsychological effect in relation to their rapid and sustained antidepressant efficacy. However, how activity at these different biochemical targets relate to changes in mood remains unknown. In this project we will start to address these unanswered questions using an integrated approach combining behavioural and molecular/cellular studies.

My research group has developed a novel translational rodent model of negative affective biases in major depressive disorder (MDD). Although biological biomarkers of MDD have not been identified, negative affective biases, where an individual’s emotional state negatively impacts on their cognition, has been suggested to represent a ‘cognitive biomarker’. We have now carefully validated a rodent model of negative affective biases in reward learning and established face, construct and predictive validity. We have also started to identify key neural and neurochemical mediators involved in regulating affective biases and found evidence of direct modulation of an ‘affective bias’ circuit by antidepressant drugs. This project aims to better understand:

1. The neural circuits which regulate affective biases and how these are modulated by psychedelics drugs.

2. The molecular and cellular mechanisms which underlie the rapid and sustained antidepressant effects of psychedelic drugs.

3. How the molecular effects of psychedelics interact with psychological processes to enhance their antidepressant effects.

The project will provide training in animal behaviour complemented by studies using ex vivo imaging methods to localise neural circuits and target manipulations using optogenetics and DREADDs-based methods.