This opinion paper (2019) proposes the use of psilocybin on patients with disorders of consciousness, since psilocybin can increase brain complexity, a possible indicator of conscious level.
“Based on its ability to increase brain complexity, a seemingly reliable index of conscious level, we propose testing the capacity of the classic psychedelic, psilocybin, to increase conscious awareness in patients with disorders of consciousness. We also confront the considerable ethical and practical challenges this proposal must address, if this hypothesis is to be directly assessed.”
Authors: Gregory Scott & Robin L. Carhart-Harris
Based on its ability to increase brain complexity, psilocybin may increase conscious awareness in patients with disorders of consciousness.
Key words: disorders of consciousness, psychedelics, complexity
Disorders of consciousness (DoC) are the most devastating form of impairment that may follow acquired brain injury. Several therapies have been proposed for patients with DoC, but none have consistently shown beneficial effects on conscious awareness or functional recovery.
Classic psychedelics, such as psilocybin, are currently undergoing significant investigation for the treatment of a range of psychiatric disorders. A scientific rationale is proposed for the use of psilocybin to increase conscious awareness in patients with DoC.
Brain Complexity and Consciousness
Complexity is a multifaceted concept that pervades many branches of the physical and life sciences. In the neurosciences, the concept of neural complexity has been proposed to explain two fundamental features of consciousness: differentiation and integration.
Several theories of consciousness have been advanced that emphasize a link between different formulations of complexity within brain activity and conscious level. These measures differ in their computational feasibility for large datasets.
Despite heterogenous definitions of complexity, the perturbational-complexity index (PCI) has been shown to robustly index conscious level across a range of states, including wakefulness, sedation, non-REM sleep and anaesthesia. Patients with locked-in syndrome show PCI levels as high as healthy awake subjects.
The PCI approach uses the Lempel-Ziv algorithm to quantify the complexity of TMS-evoked EEG responses. The Lempel-Ziv complexity measure can also be applied to spontaneous EEG recordings to differentiate between conscious and unconscious states.
We interpret LZC as a measure of variability in brain activity, and so it behaves similarly to other measures of information entropy. These related entropy-based metrics also appear to track conscious level.
Psychedelics Increase Brain Complexity
Until recently, it was assumed that brain complexity would be maximal during normal wakefulness. However, recent studies have shown that brain complexity increases during psychedelic states and that these increases are correlated with the subjective intensity of the psychedelic experience.
Increase Complexity, Increase Conscious Awareness?
Given that psychedelics increase brain complexity, could they elevate conscious awareness in patients with DoC? If not, then this would negate the relationship between consciousness and brain complexity.
Psilocybin is a prodrug of psilocin (4-hydroxy-dimethyltryptamine), and its psychoactive effects appear to be mediated by serotonin 2A (5-HT2A) receptor agonism. It has been shown to elevate measures of brain complexity in healthy humans, and many lines of evidence support the idea that psilocybin could elevate conscious awareness in patients with DoC. 5-HT2A receptor agonism is associated with enhanced cognitive flexibility in animals as well as cortical neural plasticity, whereas 5-HT2A receptor antagonism is associated with reduced cognitive flexibility and increased slow-wave sleep.
Complexity, Conscious Content and Arousal
The standard conception of consciousness is that it encompasses two inter-related dimensions: conscious content and wakefulness, or arousal. Studies of impaired consciousness suggest that LZC and related measures of brain complexity chiefly index conscious content rather than arousal, and that psychedelics increase brain complexity.
Experiments comparing psychedelics with stimulant medications may help address the question of whether drugs that promote conscious content (e.g. psilocybin) have more significant effects on brain complexity, and conscious content, than drugs that primarily promote arousal.
Conception of Consciousness
The current classification of states of consciousness uses a single scale, but recent commentaries have argued that a graded, multidimensional space would be better able to capture the full range of consciousness-related capacities.
The unidimensional conception of conscious level as indexed by brain complexity is limited by the apparent multifaceted nature of states of consciousness, and thus the multi-dimensional framework proposed here challenges this simplistic conception.
An Ethical Hypothesis?
We believe that there is a strong scientific case for research exploring the hypothesis that psychedelics can increase conscious awareness in patients with DoC. However, stern ethical objections could supervene to prevent it from being tested.
Psilocybin is a plant-based psychedelic that has been used for centuries for therapeutic purposes. It has a low toxicity and addiction potential, and is associated with positive rather than negative long-term mental health outcomes.
Several experimental interventions in DoC patients have been invasive by comparison with what we propose here, including DBS electrodes and VNS implantation.
A ‘self-awareness paradox’ could occur in patients receiving neuromodulatory treatments such as DBS and VNS, or a ‘bad trip’ could occur in patients given psilocybin. It is difficult to gauge the likelihood of either scenario in DoC patients.
Based on experience, there are ways to mitigate the risks of difficult psychological experiences. The most common adverse events were mild transient anxiety just prior to as well as during drug onset.
Previous studies have shown that psilocybin may not help patients with DoC, especially in cases of extensive neuronal loss. However, pragmatics and need should dictate how to proceed.
A potential starting point for further research into the effects of psilocybin on the brain is to test the idea in animal models of acquired brain injury. However, we doubt that this would be of any value to our hypothesis.
To assess consciousness in non-human animals, an experiment could be carried out in sedated healthy human volunteers, using scalp EEG and either LZC on spontaneous EEG signals or using PCI, accompanied by repeated behavioural measurements of consciousness. Moreover, combining spontaneous EEG/LZC and PCI measures within the same sample could potentially gain insight.
We suggest a step-wise procedure for the design of preliminary studies of psilocybin in patients with DoC, focusing on establishing safety and tolerability, and optimizing the dosage parameters, while maintaining good tolerability.
We expect to use similar patient inclusion criteria and recruitment protocol as previous early-phase pharmacology studies in this population, and will exclude patients receiving serotonergic antidepressants.
We would first aim to test the hypothesis that psilocybin increases measures of brain complexity by using a dose-escalation design. We would then aim to reach therapeutic doses in DoC patients using 5-HT2A receptor positron emission tomography.
We would record continuous scalp EEG before, during and after dosing, and calculate LZC measures of brain complexity offline. We would also record repeated cardiorespiratory observations, and carefully observe the participant for signs of psychological distress and increased sympathetic nervous system activity.
We recommend considering the choice of environment and support provided to the patient during study sessions, and timing of dosing in relation to markers of the circadian rhythm, which is likely to influence arousal.
In studies of psilocybin for patients with DoC, the Coma Recovery Scale – Revised (CRS-R) must ultimately be used as the primary outcome measure. This means that covert awareness must be tested for.
The growing evidence for pro-plasticity effects via 5-HT2A receptor agonism suggests that micro-dosing strategies may enhance standard rehabilitative care, with the aim of augmenting its effectiveness.
The nascent renaissance in psychedelic research has shed light on the study of consciousness and revealed anomalous positive effects on the complexity of brain activity.