Major depressive disorder (MDD) and alcohol use disorder (AUD) are two of the most common co-occurring disorders, with a high prevalence of AUD in patients with MDD (>23%). We and others have demonstrated potential efficacy of psilocybin-assisted psychotherapy for the treatment of either mood (Gukasyan et al., 2022; Carhart-Harris et al., 2022; Goodwin et al., 2022; Raison et al., 2023) or substance use disorders (Johnson et al., 2014, 2017; Bogenschutz et al., 2022) alone.

Patients with both illnesses may suffer, in part, from deficits in cognitive control that develop as the illness progresses (Kober & Bolling, 2014; Verdejo-Garcia, 2016; Melugin et al., 2021). Adaptive responses to the environment rely on a balance and trade-off of opponent states of cognitive control, namely flexibility and stability. Meta-control refers to our capacity to monitor and regulate this tradeoff (Eppinger et al., 2021). The development and maintenance of mood and substance use disorders may rely on disruption of meta-control and the over-learned value of stability (e.g., being stuck in rumination or drug-seeking behaviors) to the exclusion of flexibility (Morris & Mansell, 2018).

Claustrum function is altered by psilocybin (Barrett et al., 2020) and may support the instantiation of cortical brain networks to subserve cognitive control (Madden et al., 2022). We will report on preliminary therapeutic response as well as changes in both behavior and brain activity (with functional magnetic resonance imaging, or fMRI) measured before and 1 week after the administration of 25 mg psilocybin in a subset of 42 patients with MDD and co-occurring AUD, and during the acute effects of 10 mg/70 kg psilocybin in a subset of 30 healthy participants.

Reductions in both depression severity and drinking were observed from screening to 1 month after an unblinded psilocybin administration session in patients with MDD and co-occurring AUD. These patients also demonstrated an increase in effort selection during a cognitive control task from baseline to post-treatment that is associated with the strength of the mystical experience evoked by psilocybin. Healthy participants demonstrated a shift in performance of a separate cognitive control task, consistent with engagement of claustrum function, suggesting that psilocybin modulates claustro-cortical circuit function during cognitive control.

No SAEs or unexpected adverse events have been encountered in either group, and participants have well-tolerated psilocybin administration. Initial results suggest safety and substantial potential efficacy of psilocybin in reducing depression severity as well as drinking-related behaviors in patients with co-occurring MDD and AUD. These findings also support the claustrum and cognitive control as potential transdiagnostic therapeutic targets of psilocybin.