Drug addiction is a devastating personal and societal problem today. Addiction is phenomenally resistant to treatment, relapse rates remain stubbornly high and there is a huge clinical need for improved therapeutics. Several effects of drugs of abuse combine to create a perfect storm to entrap the addict. First, drugs of abuse drive the encoding of powerful associative memories that underpin compulsive behaviours and drug craving and seeking. Drugs of abuse create molecular dependence in neurons in key brain regions such as nucleus accumbens, amygdala, hippocampus and prefrontal cortex through epigenetic alterations in gene and protein expression. The molecular changes embedded by drugs of abuse fundamentally alter brain circuitry function to reduce cognitive behavioural inhibition, create low, depression-like mood states and reduce stress coping mechanisms. All these long-lasting circuitry dysfunctions contribute to maintaining the addicted state. In this project, we propose to test the ability of a range of psychedelics to reverse the molecular changes induced by chronic cocaine, heroin and alcohol treatment in the brain. We will also study the effects of a lead psychedelic agent on human iPSC-derived brain organoids from control subjects and addicts. The project will investigate the ability of psychedelic drug treatment to fundamentally ‘reset’ the molecular changes induced by a drug of abuse such as cocaine, heroin and alcohol.
