For two decades, clinicians treating alcohol use disorder watched the same ceiling materialize: medications dampened craving, behavioral therapy built coping skills, and the social fabric around the patient stayed broken. The assumption was that fixing the drinking would fix the relationships. That assumption is starting to crack, and a new pilot randomized controlled trial from medRxiv is part of the reason why.

The study enrolled recently detoxified individuals with AUD who also carried persistent depressive symptoms, then randomized them to a single 25 mg psilocybin session versus a 1 mg active placebo. Before and after the session, participants completed a visual perspective-taking task designed to measure egocentric bias, the tendency to anchor too heavily on your own visual vantage point when reasoning about what someone else can see. The 25 mg group showed meaningful reductions in that bias. The 1 mg group did not. What makes this finding worth stopping on is the specificity: psilocybin didn’t just improve mood or reduce craving scores. It shifted something in how these patients process other people.

The Social Brain in AUD Has Always Been the Harder Target

In my practice, patients with severe AUD often describe their recovery not in terms of abstinence alone, but in terms of whether they can re-enter their own families. The drinking has stopped. The relationships haven’t recovered. That gap has a neuroscientific basis. Research by Creswell and colleagues, published in Psychology of Learning and Motivation in 2023, frames this as a structural problem in social cognition: alcohol use disorder is associated with systematic disruptions in theory-of-mind processing, the very machinery the brain uses to model other people’s perspectives. Egocentric bias is one expression of that disruption. The patient who can’t accurately read the room, who misinterprets a partner’s concern as an accusation, who defaults to their own frame even when the social context demands flexibility, that patient is operating with a compromised social inference system, and no amount of naltrexone addresses it directly.

Psilocybin’s proposed mechanism here runs through the default mode network. Carhart-Harris and colleagues showed in 2012 that psilocybin reduces coordinated activity within the DMN, the network most associated with self-referential processing and the construction of a stable self-model. Ego dissolution, the subjective experience many patients describe during a psilocybin session, reflects that suppression. What this pilot adds to that picture is behavioral: the DMN quieting may translate into a measurable reduction in egocentric anchoring on specific social tasks, at least acutely. That is a more specific claim than “psilocybin improves social functioning,” and a more testable one. Having guided patients through ketamine medicine sessions, I have seen firsthand how rapid shifts in self-referential processing can reorganize a patient’s relationship to their own narrative, but ketamine’s mechanism stays largely glutamatergic, and the social cognition dimension has rarely been the focus. Psilocybin’s serotonergic 5-HT2A agonism may be doing something categorically different at the social inference level, and that distinction deserves a rigorous endpoint.

The broader pipeline context sharpens the stakes. COMPASS Pathways’ Phase 3 COMP006 trial demonstrated that 25 mg COMP360 achieved a statistically significant reduction in MADRS scores at week 6 (p<0.001), with 39% of participants in the 25 mg arm meeting response criteria in treatment-resistant depression. The Usona Institute’s Phase 2 randomized trial of single-dose psilocybin for major depressive disorder also used mood endpoints as the primary lens. These are well-designed studies, but they were built to detect what psilocybin does to the depressed self, not to the social self. For AUD specifically, those may be two different targets.

What Trial Designers Are Currently Missing

The design implication from this pilot is pointed. Psychedelic trials for substance use disorders have inherited their endpoint architecture from pharmacotherapy trials: abstinence rates, drinks-per-drinking-day, craving scales, co-occurring depression or anxiety measures. Those endpoints capture what the molecule does to consumption and to the patient’s internal state. They miss what it does to the patient’s relational capacity, which in AUD may be the more powerful predictor of sustained recovery. If the egocentric bias finding replicates in a larger sample, perspective-taking tasks and theory-of-mind batteries should become standard secondary endpoints in every Phase 2 psychedelic trial for AUD, not as exploratory add-ons, but as pre-registered co-primaries in trials that are powered to detect social cognition effects. There is also a recruitment design question embedded here: this pilot enrolled recently detoxified patients with co-occurring depressive symptoms, a dual-diagnosis population that most industry-sponsored trials systematically exclude because psychiatric complexity complicates attribution. That exclusion criterion may be protecting the statistical model at the cost of external validity. In a real-world AUD population, the overlap with depressive symptomatology is the rule, not the exception.

What I am watching for is whether any of the current Phase 2 psychedelic AUD programs add perspective-taking or social inference measures to their readout packages before they lock primary endpoints. The field has a meaningful opportunity to build social cognition into the evidence base before endpoint conventions for psychedelic-assisted therapy in AUD become entrenched around measures that were not designed to capture the mechanism this pilot identified.

References

  1. medRxiv Psychiatry, “Reduced egocentricity after psilocybin in patients with alcohol use disorder: a pilot randomized controlled trial”
  2. Creswell et al., Psychology of Learning and Motivation, 2023, “Social cognition and problematic alcohol use”
  3. Psychedelic Science, “Default Mode Network and Psychedelics: What Science Shows” (Carhart-Harris et al., 2012)
  4. Psychiatric Times, “COMP360 Psilocybin for Treatment-Resistant Depression Achieves Primary Endpoint in Phase 3 Trial”
  5. PubMed, Usona Institute, “Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial”
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Dr. Leonardo Vando, MD is Principal Investigator of Psychiatry at Vando Medical Services.