A Virtual Clinical Trial of Psychedelics to Treat Patients With Disorders of Consciousness

Disorders of consciousness (DoC) arise when severe brain injury or disruption leads to a significant reduction in awareness and the capacity for purposeful behaviour. Two major diagnostic categories are highlighted. Unresponsive wakefulness syndrome (UWS) involves sleep–wake cycles and reflexive movements but an absence of observable awareness. Minimally conscious state (MCS), by contrast, is characterised by inconsistent but reproducible signs of consciousness, including following commands or visually tracking objects. Alnagger and colleagues frame these conditions within a broader scientific context: consciousness appears to depend on the brain’s ability to generate complex, integrated, and differentiated neural activity. When this complexity deteriorates—due to structural damage or functional suppression—conscious experience diminishes. This principle is widely seen in reduced states such as deep sleep or anaesthesia, where the brain becomes more “rigid” and less able to integrate information.

The authors emphasise the role of criticality, a concept from physics describing a point between order and chaos where systems exhibit maximal complexity and responsiveness. Healthy conscious brains tend to operate near this dynamic edge. States of reduced consciousness shift the system away from this critical regime, while psychedelic states such as those produced by LSD or psilocybin push the system closer to criticality. Psychedelics act primarily on serotonin receptors, especially 5-HT2A, and previous research has connected their effects to increased neural diversity, richer perceptual experiences, and heightened network connectivity. This raises a provocative question: if psychedelics increase brain complexity in healthy individuals, might they also shift the disordered dynamics of DoC patients closer to those associated with conscious processing?

Administering psychedelics directly to DoC patients is ethically and practically challenging. Patients cannot provide consent, the substances are highly regulated, and the phenomenological consequences would be difficult to assess. Alnagger and colleagues propose a workaround: computational modelling. By combining individualised structural connectivity (from diffusion MRI) and functional connectivity (from resting-state fMRI), the authors create digital twins of each patient’s brain. These models enable “virtual pharmacology”, meaning that drug effects can be simulated by adjusting specific mathematical parameters derived from real psychedelic neuroimaging data. Through this approach, the authors aim to conduct a virtual Phase 0 clinical trial to evaluate whether LSD or psilocybin could, in theory, enhance brain complexity and shift DoC patients closer to more stable conscious dynamics.

Methods