Memory reconsolidation interference as a therapeutic mechanism of action of the serotonergic psychedelic N,N-Dimethyltryptamine

Excessive drinking and alcohol use disorder (AUD) are major mental health problems worldwide (World Health Organisation, 2018), yet the effective treatments for these conditions are few and are of use in limited subpopulations (Mekonen et al., 2021). Memory reconsolidation interference interventions have been proposed as a potential novel treatment for addictive (Milton and Everitt, 2012) and other memory-based disorders such as PTSD and phobia (e.g. Saladin et al., 2013; Brunet et al., 2008; Soeter & Kindt, 2015). Memory Reconsolidation interventions aim to weaken relapse-promoting maladaptive reward memory traces by reactivating and destabilizing these memories and interfering with their reconsolidation via pharmacological blockade or novel information (Dudai, 2006). Whilst meta-analyses have shown an overall effect size favoring memory reconsolidation interventions over control procedures (e.g. Walsh et al., 2018), both the methodology and results of individual trials are plagued by inconsistencies.

Recently, psychiatry has seen an uptick in research into the therapeutic potential of psychedelic drugs, such as psilocybin, Dimethyltryptamine (DMT), and ketamine (e.g. Carhart-Harris et al., 2021; D'Souza et al., 2022; Das et al., 2019). Preliminary research shows that psychedelic-assisted interventions may be a promising treatment for addictive disorders, potentially offering both greater and longer-lasting efficacy than existing interventions (Morgan et al., 2017). However, this nascent area of research suffers from a lack of solid theoretical foundation and no well-controlled studies investigating the fundamental mechanisms of psychedelic drugs' therapeutic effects. Memory reconsolidation has been forwarded as one such mechanism (Fattore et al, 2018; Feduccia and Mithoefer, 2018; Daneluz et al, 2022), yet while superficially appealing, there has been no adequate test of this hypothetical mechanism with serotonergic psychedelics. If reconsolidation-update is indeed a key player in the therapeutic effect of psychedelics, this will have important implications for intervention design and optimization.

The purpose of my PhD is threefold: 1) To systematically quantify methodological variability in studies of putative memory reconsolidation interference to understand key sources of effect heterogeneity and offer guidance for harmonization of methods. 2) To understand 'neuroplastic' mechanisms of serotonergic psychedelics at human-measurable scales, using DMT as a model drug in the UNITy project (see below), the largest, richest, most rigorous DMT-fMRI trial ever conducted. 3) To investigate alcohol memory reconsolidation interference as a mechanism of action of DMT in hazardous drinkers; providing a framework for further work in addictive disorders.