From compulsive behaviors to psychedelic therapeutics: When mice and man speak the same circuit language

Introduction: The inability to stop

“I couldn't stop.” Just four words, but those with obsessive–compulsive disorder repeat them like a mantra: a confession, an apology, an explanation that explains nothing.

The hand-washing continues despite bleeding skin. People keep checking things, even when they know there is no need to: like the stove is off, the door is locked, the symmetry is checked. What does the neurobiology behind this inability to inhibit entail?

For many decades, psychiatry has sought the biological anchors of compulsive behavior, running various neuroimaging suites, scouring genetic databases, and perhaps most productively, closely observing the mice that groom themselves raw. The review by Gattuso et al. in this issue represents an increasingly rare event in the current neuroscience landscape: translational convergence; preclinical models and clinical observations direct towards the same neural territory. Although we are not there yet, it indicates that we have found a target that is a valid therapeutic option (1).

A different narrative

The article draws on evidence from four clinical trials and nine preclinical trials into the effects of psilocybin on obsessive and compulsive behaviors (Figure 1). The usual psychedelic research story does not come out. Psilocybin can both cure depression and induce a mystical experience. A much more mechanistically engaging narrative about cortico-striatal circuits, behavioral inhibition, and the possibility that serotonergic psychedelics might modulate compulsivity via distinct pathways from their effects on mood.

View Figure

• Download as Powerpoint
• Download Figure

This matters.

Obsessive-compulsive disorder often does not respond adequately to frontline treatment or medications, and it afflicts two to three percent of the population. However, there is more to it than that. Compulsive behavior is a dimension that cuts across diagnostic boundaries. It manifests in addiction, eating disorders, body dysmorphic disorder, Tourette syndrome, and even the rigid cognitive patterns of the autism spectrum conditions.

The translational achievement: Cross-laboratory replication

This translational success is of special interest. Laboratory studies in Israel and Australia, and later validation studies, have independently observed a remarkable finding in SAPAP3 knockout mice: a single dose of psilocybin produces sustained anti-grooming effects for 1-7 weeks (2, 3). To put this finding in context, these mice are genetically engineered to lack the protein SAPAP3 (a postsynaptic scaffolding molecule highly expressed in the striatum), and groom themselves excessively (to the point of self-harm). Critically, this excessive grooming in mice is accompanied by cortico-striatal dysfunction, which models the circuit-level dysfunction found in humans with obsessive-compulsive disorder (4). When independent laboratories observe the same therapeutic effect in the same genetic model, using different doses and assessment timepoints, neuroscience takes notice. Preclinical psychopharmacology is a field where replication is now the exception rather than the rule.

This collaboration between labs matters because it addresses the reproducibility crisis in behavioral neuroscience. Too often, one exciting result creates a new subfield that later collapses with a wave of failed replications. We have independent teams here, asking similar questions, using similar methods, getting similar answers.

Bidirectional flow: From bedside to bench and back

What makes this systematic review truly translational is the smooth two-way flow of insights between the bedside and the bench. The clinical observations came first. This pioneering study, reported in 2006 by Moreno and colleagues, found that single doses of psilocybin rapidly reduced obsessive-compulsive symptoms in nine patients with treatment-resistant OCD. Specifically, the effects were observed between four and twenty-four hours post-administration (5). More recently, Schneier and colleagues found that a 25 mg dose significantly reduced symptoms of body dysmorphic disorder at multiple time points, extending to 12 weeks, with large effect sizes (6). In the most methodologically sophisticated clinical study to date, Pellegrini and colleagues found that 10 mg psilocybin rapidly reduced symptoms in adults with moderate-to-severe OCD. In that study, compulsions improved more robustly than obsessions (7).

Among the plethora of notable clinical observations, one issue has crossed researchers' minds that only preclinical work can answer: are these effects genuine pharmacological phenomena, or due to placebo, expectancy, and extensive psychological support given during any psychedelic trial? The answer from rodent studies is unambiguous. Mice have no expectations about psychedelic therapy. They receive no preparatory therapy, no integration sessions afterward, no cultural narratives about mystical experiences catalyzing personal transformation. Yet, the anti-compulsive effects appear robust.

This tells us something important: the biological substrate matters. The way psilocybin works in reducing compulsive behaviors is likely to be more than mere suggestion and more than the subjective psychedelic experience.

The mechanistic mystery: Beyond 5-HT2A

So, what is the mechanism that makes this an interesting story and not just an uplifting one? Research has shown that the anti-compulsive actions of psilocybin can be achieved without 5-HT2A receptor activation. Gattuso and colleagues highlight this in multiple studies (8, 9). In other words, the main target thought to mediate the psychedelic experience is not responsible for these effects. What's more, when researchers pre-treated animals with selective 5-HT2A antagonists that completely block these hallucinogenic-like behaviors, there remains a reduction in compulsive behaviors. According to this finding, which multiple research groups have replicated, we may have pharmacological agents that act via different mechanisms.

The 5-HT2A receptor has become too central to the field. Everything psychedelic is attributed to it, which makes no sense. The present evidence suggests otherwise. Psilocybin may diminish compulsivity via 5-HT2C receptor effects, modulation of striatal glutamatergic signaling, actions on BDNF pathways, or mechanisms yet to be conceived. The uncertainty here is not a weakness but an opportunity. When blocking the presumed mechanism of action does not block the therapeutic effect, the molecule provides us with new insights into how the brain works.

Practical implications: Scalability without the trip

One practical implication deserves emphasis. If the anti-compulsive effects work independently of 5-HT2A activation, they could work in a setting that does not require the heavy-duty psychedelic experience that today mandates clinic oversight, special setting, and hours of therapist time. Kiilerich et al. observed that multiple doses of psilocybin below the hallucinogenic threshold decreased grooming behavior in rats while increasing synaptic markers in the paraventricular thalamus of the same species (10). This raises the question of whether treatment paradigms can be developed that retain therapeutic efficacy while eliminating the subjective effects that limit scalability and accessibility.

Methodological honesty: Acknowledging limitations

However, we must temper enthusiasm with methodological honesty. The limitations of the clinical studies described here are common. The three main trials involved only 9, 12, and 19 participants, a small sample size. Most clinical trials did not include a placebo control group. The retrospective survey conducted by Buot et al. among 135 psilocybin mushroom consumers is subject to the selection bias inherent in web-based self-report (11). Most troublesome is the blinding issue: when a drug induces drastic changes in consciousness, participants know whether or not they received the active drug. Even sophisticated active placebos cannot mimic the subjective psychedelic effects. The contribution of expectancy and placebo to the observed effects is yet to be quantified.

Preclinical literature methodology tends to be stronger; however, it has its own translational issues. Rodents can model compulsions (behaviors), but they cannot model obsessions (thoughts, ruminations, mental compulsions). According to the Pellegrini clinical data, it appears that although obsessions showed less improvement, compulsions were addressed more effectively (7). Most probably, psilocybin exerts a beneficial effect on the cortico-striatal circuitry of the brain. This plays a relevant role in selecting patients and in setting realistic expectations for outcomes.

Studies on mice and humans have shown temporal discrepancies. In rodent models, single-dose effects persist for weeks. In humans, benefits begin to fade within one to four weeks. Why? Do mice not have the ongoing psychological stressors, relationship problems, workplace issues, and existential questions that keep sustaining symptomatology in humans? Or do the measurement instruments differ in sensitivity? It is also possible that the compulsive grooming observed in SAPAP3 mice is a more pure neurobiological phenomenon than the complex psycho-social-biological entity known as OCD we diagnose in our human patients.

The road ahead: A clear research agenda

Where does this leave the field? According to the systematic review by Gattuso and colleagues, a clear research agenda emerges from a genuine confrontation with limitations. There is a need for randomised controlled trials with sample sizes sufficient to detect clinically meaningful effects and exclude placebo effects. The ongoing study by Ching et al. (planned enrollment of 36 participants with OCD, using niacin as an active placebo, psychedelic-naive participants) is the next methodological generation study (12). We need mechanistic neuroimaging studies exploring how psilocybin alters cortico-striatal connectivity and whether normalization of circuit hyperactivity predicts symptom response. We require studies that optimize doses for comparison. We may, therefore, most urgently require studies that properly include sex as a biological variable, as evidence emerges of sex-specific psilocybin responses.

We also require something equally important yet more difficult to implement: studies that test psilocybin across the entire range of compulsive disorders. The Schneier research into body dysmorphic disorder is a beginning (6). And then what of trichotillomania, dermatillomania, and hoarding disorder? The compulsive drug-seeking of addiction, the repetitive behavioral patterns in autism, the motor and vocal tics of Tourette syndrome—what about these? If psilocybin really does modulate a trans-diagnostic dimension of compulsivity, then cross-testing in these disorders would reveal if we have identified a core mechanism or just a disorder-specific effect.

Conclusion: A legitimate starting point

The translational paradigm offered in this review is a model for how psychedelic science can evolve beyond its present state of small open-label trials and enthusiastic testimonials. Clinical observations generate hypotheses. Preclinical models evaluate mechanisms in settings that eliminate confounders. Understanding mechanics helps to develop more advanced clinical trials. Each domain checks the other's limitations. Each domain answers questions that the other cannot address. This iterative, bidirectional process is how pharmacology advances from serendipitous observation to rational therapeutics.

We began with patients who could not stop. We end with mice that also could not stop, until a single dose of a compound changed something in their striatum, allowing behavioral flexibility to return. The distance between mouse and human remains vast, spanning chasms of consciousness, subjectivity, and social context that no amount of circuit mapping can fully bridge. Yet, when both species share the same neural architecture and respond to the same molecule in ways that parallel each other, science has found a handhold. Not certainty. Not cure. But a legitimate starting point for the careful work of translation.