Apomorphine and psilocybin to improve recovery from coma in the intensive care unit: protocol for a prospective, open-label, dose-escalation study.
Anna Kristina Eigenbrodt, Poul P Laigaard, Melika Hassani, Marwan H Othman, Moshgan Amiri, Kirsten Møller, Jesper Kjaergaard, Daniel Kondziella
BMJ Open September 22, 2026 DOI: 10.1136/bmjopen-2026-124508 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase 1b, prospective, open-label, bicentric, dose-escalation clinical trial protocol Randomized Peer reviewed |
|---|---|
| Sample size | 80 |
| Population | ICU patients with disorders of consciousness after brain injury |
| Interventions | Psilocybin Apomorphine |
| Dose | Cohort 1: 1 mg psilocybin; Cohort 2: 10 mg psilocybin; Cohort 3: 25 mg psilocybin; all patients: 2 mg subcutaneous apomorphine one hour after psilocybin |
| Duration | Awakening assessed within 30 days; functional outcome at 90 days |
| Measures | Clinical scales (unspecified), automated pupillometry, electroencephalography, functional outcome at 90 days |
| Topics | Psilocybin |
| Keywords | Adult neurology Brain injuries Clinical trial |
| Key findings | The authors hypothesize that combining apomorphine (targeting arousal) and psilocybin (targeting awareness) is safe in ICU patients with disorders of consciousness and may reveal cerebral reserves after brain injury. The trial will assess safety and potential efficacy, with time to awakening within 30 days as the primary outcome. |
Abstract
Recovery of consciousness after brain injury remains a major challenge in the intensive care unit (ICU), and pharmacological treatments that directly promote awakening from coma and other disorders of consciousness (DoC) are lacking. We hypothesise that simultaneously targeting the two core components of consciousness by pharmacological means-arousal with apomorphine and awareness with psilocybin-is safe in the ICU and may facilitate evidence of cerebral reserves after brain injury. This trial aims to evaluate the safety and potential efficacy of apomorphine and psilocybin in unresponsive ICU patients with brain injury. We will conduct a prospective, open-label, bicentric, phase 1b, dose-escalation study enrolling 80 ICU patients with DoC. Participants will be allocated to three dose-escalation cohorts. Cohort 1 (n=26) will receive 1 mg psilocybin, Cohort 2 (n=27) 10 mg psilocybin and Cohort 3 (n=27) 25 mg psilocybin. One hour after psilocybin, all patients will receive 2 mg subcutaneous apomorphine. Primary outcome is time to awakening within 30 days. Secondary outcomes are serious somatic and neuropsychiatric adverse events. Exploratory outcomes comprise changes in consciousness assessed by clinical scales, automated pupillometry, electroencephalography activity and functional outcome at 90 days. An independent Data Safety Monitoring Board will conduct interim analyses prior to dose escalations. The trial was authorised by the Danish Medical Research Ethics Committees and the Danish Medicines Agency through the Clinical Trials Information System (EU CT number 2023-503617-30-02). The study is considered to involve relatively low risk with the potential to improve future treatment options for DoC patients. If psilocybin and apomorphine are shown to be safe, this would justify a larger multicentre randomised trial to evaluate clinical efficacy. Findings will be disseminated through peer-reviewed journals and scientific conferences. 2023-503617-30-02.
Comparable studies
Other non-randomized and open-label trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Patients with moderate-to-severe, unipolar, treatment-resistant major depression | 2016 | Open-label feasibility trial | n = 12 |
| Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Patients with severe, unipolar, treatment-resistant major depression | 2017 | Open-label trial | n = 20 |
| Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction Psychiatrically healthy nicotine-dependent smokers | 2014 | Open-label pilot study | n = 15 |
| Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Patients with treatment-resistant depression | 2018 | Clinical trial | n = 20 |
| Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder Subjects with obsessive-compulsive disorder (OCD) | 2006 | Controlled clinical trial |
Citations in the library
Cites 34
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- A Theoretically Based Index of Consciousness Independent of Sensory Processing and Behavior Science Translational Medicine August 14, 2013
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
and 29 more in the library