Neuroscience of Consciousness, 2019, 5(1): niz003

doi: 10.1093/nc/niz003
Opinion Paper

Psychedelics as a treatment for disorders of

consciousness

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Gregory Scott1,* and Robin L. Carhart-Harris1,2
1
Department of Medicine, The Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of
Brain Sciences, Imperial College London, 3rd Floor, Burlington Danes Building, Hammersmith Hospital, Du
Cane Road, London W12 0NN, UK; 2Department of Medicine, Centre for Psychedelic Research, Division of
Brain Sciences, Imperial College London, 5th Floor, Burlington Danes Building, Hammersmith Hospital, Du
Cane Road, London W12 0NN, UK
*Correspondence address. Department of Medicine, The Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences,
Imperial College London, 3rd Floor, Burlington Danes Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Tel: þ44 (0)7909 691484;
E-mail: gregory.scott99@imperial.ac.uk

Abstract
Based on its ability to increase brain complexity, a seemingly reliable index of conscious level, we propose testing the capac-
ity 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.

Key words: disorders of consciousness; psychedelics; psilocybin; complexity

Introduction Classic psychedelics are currently undergoing significant in-

vestigation for the treatment of a range of psychiatric disorders
Disorders of consciousness (DoC) are the most devastating form (Carhart-Harris and Goodwin 2017). Here, we propose that the
of impairment that may follow acquired brain injury. In con- classic psychedelic, psilocybin, be explored as a treatment to in-
trast to comatose patients, those in the vegetative state (VS) crease conscious awareness in patients with DoC. A scientific
and minimally conscious state (MCS) exhibit signs of wakeful- rationale is proposed based on findings from research into the
ness (eye opening). VS patients show no overt signs of aware- neurobiology of DoC and the effects of psychedelics.
ness, whereas MCS patients show minimal but clearly Developments in these hitherto separate fields of inquiry now
discernible behavioural evidence of awareness. A range of ther- suggest a potential therapeutic avenue, based on the twin dis-
apies have been proposed for patients with DoC, including phar- coveries that measures of brain complexity reliably index con-
macological (e.g. zolpidem, amantadine) (Gosseries et al. 2014), scious level, and that brain complexity can be increased by
invasive- [e.g. deep brain stimulation (DBS) (Vanhoecke and psychedelics (Fig. 1).
Hariz 2017), vagal nerve stimulation (VNS) (Corazzol et al. 2017)]
and non-invasive electrical stimulation [e.g. transcranial direct
current stimulation (Thibaut et al. 2014)], and transcranial mag-
netic stimulation (TMS) (Pistoia et al. 2013). However, no treat-
Brain Complexity and Consciousness
ments have consistently shown beneficial effects on conscious Complexity is a multifaceted concept that pervades many
awareness or functional recovery (Royal College of Physicians branches of the physical and life sciences. In the neurosciences,
2013; Giacino et al. 2014; Vanhoecke and Hariz 2017). many theoretical accounts of consciousness have related the

Received: 3 September 2018; Revised: 6 March 2019. Accepted: 6 March 2019

C The Author(s) 2019. Published by Oxford University Press.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

1
 2 | Scott and Carhart-Harris

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Figure 1. Brain complexity, consciousness and psychedelics. (A) Measures of brain complexity index conscious level. Empirical measures of
brain complexity are high in the normal awake state and low whenever consciousness is lost. In the case of the perturbational complexity in-
dex (PCI Casali et al. 2013), a pulse of transcranial magnetic stimulation (TMS) provides a cortical perturbation and the evoked electroencepha-
logram (EEG) responses are recorded. Alternatively, spontaneous EEG data alone are recorded. The Lempel-Ziv algorithm, a measure of
compressibility, quantifies the complexity (LZC) in the thresholded EEG data (illustrated by black and white grids). LZC values robustly index
conscious level. VS ¼ vegetative state; MCS ¼ minimally conscious state; EMCS ¼ emergence from MCS; LIS ¼ locked-in syndrome; LZC ¼
Lempel-Ziv complexity; non-REM ¼ non-rapid eye movement sleep; PCI ¼ perturbational-complexity index. (B) Psychedelics increase brain
complexity above normal levels. Classic psychedelics increase brain complexity measures like LZC above the levels in the normal awake state.
This raises the possibility that psychedelics could increase conscious awareness in patients with disorders of consciousness, where brain com-
plexity is low. LSD ¼ lysergic acid diethylamide.

complexity of dynamics in a neural system to the manifestation each subset and the rest of a system. Tononi and Edelman pos-
of conscious experiences (Tononi et al. 1994; Edelman 2009; ited that during conscious awareness, ‘heterogeneous patterns
Ruffini 2017; Carhart-Harris 2018). One influential formulation of short-term correlations within the corticothalamic system
has been that of neural complexity, proposed by Tononi and will result in [high neural complexity]’ (Tononi et al. 1994).
Edelman in 1994 (Tononi et al. 1994). This concept accounts for Several theories of consciousness have since been advanced
two fundamental features of consciousness, namely differentia- that emphasize a link between different formulations of com-
tion, the property that any particular experience is composed of plexity within brain activity and conscious level. Alongside
many different components and is distinguishable from any these theoretical developments has been the introduction of a
other experience, and also integration, the property that any wide range of measures of dynamical complexity. These various
given conscious experience involves the integration of compo- measures reflect the diversity of definitions of complexity in
nents into a unified whole. Importantly, neural complexity use [for review, see Arsiwalla and Verschure (2018), Seth et al.
could, in principle, be calculated empirically, as the average mu- (2006); see also Bassett and Gazzaniga (2011), Cocchi et al. (2017)
tual information—a measure of information sharing—between for broader reviews in complex systems theory] and differ in the
 Psychedelics as a treatment for disorders of consciousness | 3

extent to which they directly capture the properties of differen- psychedelic state exceed those found in normal waking con-
tiation versus integration, as well as temporal versus spatial sciousness (Fig. 1B). Specifically, in human subjects, increases in
complexity, and in their computational feasibility for large brain complexity (LZC) in excess of those seen in normal wakeful-
datasets. ness were observed with psilocybin, lysergic acid diethylamide
Despite heterogenous definitions of complexity, a prediction (LSD) and ketamine (at ‘psychedelic-like’ doses) (Schartner et al.
shared by many theories of consciousness is that complexity 2017a). This finding has been replicated using a variety of com-
should be high in the normal awake state and low whenever plexity measures and measurement tools, including EEG, mag-
consciousness is lost, be it through anaesthesia, non-rapid eye netoencephalography and functional MRI [see Carhart-Harris
movement (REM) sleep, or acquired brain injury. In the past two (2018) for review]. Furthermore, the magnitude of complexity
decades, a raft of empirical support for these predictions has increases correlated with the subjective intensity of the psy-
emerged. Massimini and colleagues have provided striking evi- chedelic experience (Schartner et al. 2017).
dence in favour of the principle via use of the so-called pertur-
bational-complexity index (PCI). PCI quantifies the complexity
Increase Complexity, Increase Conscious

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of electroencephalogram (EEG) responses to pulses of TMS
(Fig. 1A) (Casali et al. 2013). This perturbational approach has
Awareness?
been likened to hitting a bell and measuring the complexity of Given that impairments in conscious awareness appear to
the reverberations that follow. The PCI has been shown to ro- closely relate to reductions in measures of brain complexity and
bustly index conscious level across a range of states, including psychedelics robustly increase brain complexity, could psyche-
wakefulness (where the PCI is highest), sedation, non-REM sleep delics elevate conscious awareness in patients with DoC?
and anaesthesia. In patients with DoC, the PCI is lowest in VS Note that this hypothesis does not require that brain com-
patients, followed by patients in the MCS, then those emerged plexity be the cause of conscious awareness. Brain complexity per
from MCS (denoted EMCS). In contrast, patients with locked-in se may rather, in the terminology of Seth and Edelman (2009), be
syndrome, who have intact conscious awareness but cannot re- an explanatory correlate of the neural processes intimately related
spond motorically, show PCI levels as high as healthy awake to conscious awareness. With this qualification in mind, a key
subjects (Casali et al. 2013). question for our proposal is whether it is possible to increase
At the heart of the PCI approach is quantification of the com- measures of brain complexity without increasing conscious
plexity of TMS-evoked EEG responses using an implementation of awareness. If it were possible, then this would negate our hy-
the Lempel-Ziv algorithm, a measure of compressibility which pothesis and call into doubt the relationship between conscious-
counts the number of unique patterns in a sequence, hence its ev- ness and brain complexity, at least as we define it here.
eryday use in compressing large computer files (‘zipping’). The classic psychedelic, psilocybin, is currently undergoing
Importantly, the Lempel-Ziv complexity (LZC) measure can also be substantial clinical investment (Carhart-Harris and Goodwin
applied to EEG recordings of spontaneous brain activity, i.e. with- 2017). Psilocybin is a prodrug of psilocin (4-hydroxy-dimethyl-
out TMS perturbation. Whilst there are substantial differences be- tryptamine), whose principal psychoactive effects appear to be
tween the spontaneous and perturbational approach, particularly mediated by serotonin 2A (5-HT2A) receptor agonism. Psilocybin
that PCI evaluates only the complexity of deterministic responses elevates measures of brain complexity in healthy humans
of the cortex to TMS (Casali et al. 2013), the LZC of spontaneous (Schartner et al. 2017a; Carhart-Harris 2018) and many other
EEG also effectively differentiates between conscious and uncon- lines of evidence support the idea that psilocybin could elevate
scious states [including anaesthesia (Bai et al. 2015; Schartner et al. conscious awareness in patients with DoC. The 5-HT2A recep-
2015) and sleep (Schartner et al. 2017b)]. In DoC, LZC-based values tors have their densest expression in the high-level cortical
of spontaneous EEG reliably discriminate VS from MCS patients areas belonging to the default-mode network, which has been
(Wu et al. 2011; Sitt et al. 2014) and values increase monotonically strongly implicated in conscious processing as well as the psy-
with patients’ conscious level (Sitt et al. 2014). chedelic state (Guldenmund et al. 2012; Beliveau et al. 2017;
Our interpretation of these spontaneous EEG results is that Carhart-Harris 2018). Most 5-HT2A receptors are expressed post-
LZC principally captures the variability or diversity of brain activ- synaptically on layer 5 pyramidal neurons (Berthoux et al. 2018).
ity (i.e. differentiation rather than integration), and so behaves These large, deep layer neurons are known to be key integration
similarly to other measures of information entropy (i.e. capturing units in the cortex, and are the only cell type with dendrites
signal diversity over time). These related entropy-based metrics spanning all cortical layers (Shai et al. 2015). In addition, presyn-
also appear to track conscious level [see Schartner et al. (2015), aptic 5-HT2A receptors located at thalamo-cortical synapses
Carhart-Harris (2018) for further discussion]. Please see Schartner have been shown to play an important role in the control of
et al. (2015) and Mediano et al. (2019) for further discussion of thalamo-frontal connectivity, also known to be important for
these topics, and note that, for the sake of disambiguation, from consciousness (Giacino et al. 2014; Barre et al. 2016). 5-HT2A re-
here on, when we refer to ‘complexity’ we are referring to the ‘dif- ceptor agonism in animals is associated with enhanced cogni-
ferentiation’ component in the original conception of ‘brain com- tive flexibility as well as cortical neural plasticity (Frankel and
plexity’, i.e. the component that is measurable via LZC or a Cunningham 2002; Boulougouris et al. 2008; Furr et al. 2012;
related entropy-based metric. Zhang and Stackman 2015; Ly et al. 2018; Olson 2018) whereas 5-
HT2A receptor antagonism is associated with reduced cognitive
flexibility and increased slow-wave sleep (Carhart-Harris and
Psychedelics Increase Brain Complexity Nutt 2017). We recognize that one should be cautious when ex-
Until recently, it was generally assumed that, in terms of states of trapolating from findings in animals to humans. However, there
consciousness, brain complexity would be maximal during nor- is some tentative evidence that cognitive flexibility is also en-
mal wakefulness, since all other tested states of reduced con- hanced in humans under psychedelics (Kuypers et al. 2016), al-
sciousness (e.g. non-REM sleep, anaesthesia, DoC) feature though we would be hesitant to infer from this that
correspondingly lower complexity values. It was therefore remark- psychedelics can enhance cognitive performance [see also
able to discover that brain complexity values recorded during the Bayne and Carter (2018) and Carhart-Harris and Nutt (2017)].
 4 | Scott and Carhart-Harris

Complexity, Conscious Content and Arousal seizures and the psychedelic state—in that it fails to do justice
to the evidently multifaceted nature of these states (Bayne et al.
The standard conception of consciousness is that it encom-
2016; Bayne and Carter 2018). We are sympathetic to this view
passes two inter-related dimensions (Laureys et al. 2009;
but also mindful of the pragmatic value of simple guiding prin-
Boly et al. 2013): (i) the ‘content’ of consciousness, thought to be
ciples in science. Thus, it remains to be seen how such a multi-
primarily related to cortical mechanisms, and (ii) wakefulness,
dimensional framework, the details of which remain somewhat
or arousal, which subserves (i) and is controlled by the ascend-
underspecified (Bayne et al. 2016), will align with the unidimen-
ing activation systems of the brainstem and basal forebrain
sional complexity measures such as PCI and LZC that dominate
(i.e. the reticular activating system) (Boly et al. 2013). A key
empirical studies of states of consciousness and indeed current
question is: how do these dimensions relate to measures of
theories of consciousness (Baars 2005; Tononi et al. 2016;
brain complexity like LZC?
Carhart-Harris 2018). As we acknowledged earlier, we see our
Studies of impaired consciousness suggest that LZC and re-
proposal (to explore psychedelics as a treatment in DoC) as a
lated measures of complexity chiefly index conscious content
challenge to the unidimensional conception of conscious level
rather than arousal, e.g. as shown by the reductions in LZC that

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as indexed by brain complexity, in that to find a dissociation be-
differentiate VS from MCS patients (Casali et al. 2013; Sitt et al.
tween complexity increases and conscious awareness would
2014) and non-REM from REM sleep (Abásolo et al. 2015). To our
suggest important limitations to this simplistic framework.
knowledge, there is no evidence that stimulant drugs, such as
D-amphetamine or methylphenidate, which primarily increase
arousal, increase brain complexity measures. In the case of psy-
chedelics, our own experience is that arousal provides minimal An Ethical Hypothesis?
explanatory value for describing the quality of the psychedelic
We believe that the evidence presented here suggests a strong
experience. Moreover, we have argued that the evidence over-
scientific case for research exploring the hypothesis that psy-
whelmingly suggests that psychedelic-related elevations in LZC
chedelics can increase conscious awareness in patients with
or information entropy (to which LZC is closely and formally re-
DoC. However, stern ethical objections could supervene to pre-
lated) reflect an increased richness of conscious experience
vent it from being tested. Ethical consideration of any interven-
(Carhart-Harris 2018). Together, these observations suggest that
tional research in patients with DoC must grapple with dual
targeting increases in conscious content, rather than (or per-
opposing imperatives: on the one hand are concerns about risks
haps in addition to) arousal, may be key to increasing conscious
of harm to patients lacking the capacity to consent; and on the
awareness in DoC patients.
other hand, is the principle that research must be done if we are
Experiments comparing psychedelics with stimulant medi-
ever to progress in our ability to improve the health of these
cations may help address the question of whether drugs pre-
patients. We agree with others who have argued that the inabil-
supposed (here) to increase conscious content (e.g. psilocybin)
ity of patients to consent doesn’t make research ethically illegiti-
have more significant effects on brain complexity, and con-
mate so long as it is ethically proportionate, a judgement that
scious content, than drugs that primarily promote arousal.
hinges on the accurate assessment of risks and benefits
Neurotransmitter systems implicated in the regulation and
(Giacino et al. 2014; Fins et al. 2008).
maintenance of arousal include noradrenaline, dopamine, ace-
Contrary to the alarmist campaigning that so negatively af-
tylcholine, orexin, adenosine, histamine and 5-HT (Boutrel and
fected perceptions of psychedelics during and after the 1960s,
Koob 2004; Ciurleo et al. 2013; Mura et al. 2014). Most classic
plant-based psychedelics have been used for centuries for ther-
stimulants act on catecholamines, and drugs such as D-am-
apeutic purposes, and a recent resumption of clinical research
phetamine (Zhang et al. 2009), levodopa (Krimchansky et al.
with them has established conditions for their safe administra-
2004) and modafinil (Dhamapurkar et al. 2017) have been used
tion. Psilocybin has a particularly favourable safety profile, with
in DoC patients, with evidence of modest and variable clinical
a low toxicity and addiction potential (Passie et al. 2002;
effects [see Ciurleo et al. (2013) and Mura et al. (2014) for review].
Carhart-Harris and Goodwin 2017). Evidence clearly indicates
Our working hypothesis is that psilocybin is able to enhance
that, contrary to a popular misconception, psychedelics, when
conscious awareness to a greater extent than these stimulant-
used with the relevant safeguards in place, are associated with
based alternatives.
positive rather than negative long-term mental health out-
comes (Carhart-Harris and Goodwin 2017). There is now con-
verging support for the safety and tolerability of psilocybin in a
The Relevance of a Multidimensional
variety of psychiatric disorders [e.g. see Carhart-Harris and
Conception of Consciousness Goodwin (2017) for review]. The psychedelic effects of psilocybin
The current classification of DoC uses a taxonomy of states of are detectable 30–60 min after oral dosing (10–25 mg), peaking
consciousness ordered along a single scale, i.e. with EMCS at 2–3 h, and subsiding to negligible levels at least 6 h post-dose
patients having a higher level of consciousness than MCS (Carhart-Harris et al. 2016). Intravenous administration acceler-
patients who, in turn, have a higher level of consciousness than ates the onset into the domain of seconds and shortens the du-
VS patients. However, recent challenges to this standard unidi- ration of the experience considerably (Turton et al. 2014).
mensional construct of ‘levels of consciousness’ have been pro- Several experimental interventions in DoC patients have
posed (Bayne et al. 2016, 2017; Bayne and Carter 2018). These been invasive by comparison with what propose here. For ex-
commentaries argue that the full range of consciousness- ample, the surgical implantation of DBS electrodes has been
related capacities would be better classified using a graded, carried out for 50 years, despite a lack of consistent evidence of
multidimensional space that captures, e.g. cognitive, sensory, benefits for improving conscious awareness (Vanhoecke and
affective and behavioural characteristics (Bayne et al. 2017). The Hariz 2017). Recently, VNS implantation has been reported in a
same criticism has been levelled to applying the ‘levels of con- single case of a VS patient. Only modest behavioural improve-
sciousness’ construct to all global states of consciousness—e.g. ments were observed when stimulation levels were titrated
alert wakefulness, REM sleep, general anaesthesia, absence over a 6-month period (Corazzol et al. 2017).
 Psychedelics as a treatment for disorders of consciousness | 5

A special ethical concern for neuromodulatory treatments potentially gain insight into their inter-relatedness or indeed
such as DBS and VNS has been the possibility of a ‘self-aware- separation and differential relevance for conscious awareness.
ness paradox’, whereby through an increase in conscious Whilst there are fundamental difficulties in extrapolating
awareness, the patient experiences a concomitant increase in findings from sedated volunteers to patients with DoC, positive
awareness of his/her clinical predicament and disability (Schiff findings would support the case for a study of psilocybin in DoC
et al. 2009). For psilocybin, treatment could conceivably also in- patients. A related experiment in humans could be carried out
duce a transient unpleasant state of awareness, sometimes re- in sleep, testing the hypothesis that psychedelics increase com-
ferred to colloquially (although not always accurately or plexity and conscious level in non-REM sleep, perhaps by pro-
helpfully) as a ‘bad trip’. It is difficult to gauge the likelihood or moting REM sleep, evidence for which can also be found in the
nature of either scenario in DoC patients given a psychedelic. A historical literature (Muzio et al. 1966; Torda 1968). Experiments
low baseline level of awareness might intuitively imply that un- comparing psilocybin with stimulant medications would help
pleasant psychological phenomena will be both less likely and answer the question of whether drugs presupposed to increase
less severe than in fully aware subjects. Our experience is that conscious content (e.g. psilocybin) have more significant effects

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such phenomena are rare in the investigational context, but on brain complexity and conscious awareness than drugs that
more likely at higher doses and in settings lacking in psycholog- more specifically promote arousal.
ical support.
Based on experience and accumulating evidence, there ap-
pear to be ways to mitigate the risks of difficult psychological
Experimental Considerations
experiences (Carhart-Harris et al. 2018). In our Phase 2 study in Assuming the scientific, ethical and regulatory case can be won
treatment-resistant depression, psychologically supported ad- for the testing of our hypothesis, we suggest some principles for
ministration of oral psilocybin (10–25 mg) was well-tolerated by the design of preliminary studies of psilocybin in patients with
all patients, with the most common adverse events being mild DoC, based on our experience of psychedelic experimental
transient anxiety just prior to as well as during drug onset research.
(Carhart-Harris et al. 2016). In the case of DoC patients, one We would advocate an incremental and adaptive approach,
might expect anticipatory anxiety to be lower than in neurotypi- where the first steps would be to establish safety and tolerabil-
cal individuals and the risk of anxiety could be further reduced ity and examine the signal changes of interest (i.e. changes in
by careful attention to the environment and ensuring familiar LZC in spontaneous EEG activity). This step-wise procedure
carers are at hand during dosing. would then be followed by a focus on optimizing the dosage
parameters, and measuring and searching for the desired
behavioural effects, i.e. an observable increase in conscious
awareness, while maintaining good tolerability.
Future Horizons We expect that the patient inclusion criteria and recruitment
The modest outcomes from previous interventional studies in protocol would be similar to previous early-phase pharmacol-
patients with DoC should temper optimism that psilocybin ogy studies in this population. Exclusion criteria should include
could bring clinically meaningful benefits, particularly in cases a history of psychotic disorder, as is typical with psychedelic re-
of extensive neuronal loss, e.g. a sufficient degree of functional search, and an abnormal resting electrocardiogram.
neuronal architecture may need to be in place for psychedelics Serotonergic antidepressants have been found to downregulate
to elicit a functionally meaningful effect. However, we believe the 5-HT2A receptor, and attenuated responses to psychedelics
that pragmatics and need, supported by sound theory and evi- have previously been reported in individuals chronically medi-
dence, as well as proper consideration of ethics and care, should cated with serotonergic antidepressants (Bonson et al. 1996). We
dictate how to proceed. would therefore exclude any patients receiving these drugs or
One potential starting point might be to test the idea using request controlled washout from these medications, for which
animal models, but we are doubtful of its translational value to we have a working protocol.
our hypothesis. While animal studies have informed our under- As outlined above, we would first aim to test the hypothesis
standing of the neural circuitry involved in information proc- that psilocybin increases measures of brain complexity. To do
essing in general (Boly et al. 2013), it is less evident that any this safely, we would use a dose-escalation design, using low
existing animal model of acquired brain injury (i.e. either severe doses to assess tolerability before moving to a higher, poten-
traumatic brain injury or adult hypoxic ischaemic injury) holds tially therapeutic dose range. Doses in the range of 25–40 mg are
relevance for the goal of understanding the recovery of con- used clinically and have been found to induce profound, exis-
scious awareness in human individuals with DoC. An alterna- tentially ‘transformative’ experiences in both healthy and clini-
tive to injury models would be to test in sedated animals cal populations. The physiological safety of 30 mg/70 kg
whether psilocybin increases measures of brain complexity psilocybin has been well-demonstrated in healthy volunteers
from a baseline of sedative-induced reduced complexity. (Griffiths et al. 2006). We would therefore aim to reach such
Intriguingly, evidence of this kind can be found in the literature doses, particularly as it is possible DoC patients have reduced
from the 1950s, with a report that LSD reverses the sedating sensitivity to the effects of psilocybin. Although it would add
effects of anaesthetic doses of barbiturates in cats (Apter 1958). complication to procedures, 5-HT2A receptor positron emission
Given the difficulties in assessing consciousness in non- tomography could allow this assumption to be tested empiri-
human animals, an advance on this would be to carry out the cally (Kumar and Mann 2014).
experiment in sedated healthy human volunteers, measuring We would, as a minimum, record continuous scalp EEG be-
complexity with scalp EEG and either LZC on spontaneous EEG fore, during and after dosing, and calculate LZC measures of
signals or using PCI, accompanied by repeated behavioural brain complexity offline. If practicable, it would be beneficial to
measurements of consciousness, before and after psilocybin ad- additionally use the PCI (i.e. EEG combined with TMS) (Casali
ministration. Moreover, by combining spontaneous EEG/LZC et al. 2013). Alongside neurophysiological measures, we would
and PCI measures within the same sample, one could also record repeated cardiorespiratory observations (heart rate,
 6 | Scott and Carhart-Harris

blood pressure, respiratory rate) and carefully observe the par- but also significant ethical and pragmatic challenges. The na-
ticipant for signs of psychological distress and increased sym- scent renaissance in psychedelic research has shined a light on
pathetic nervous system activity. For an early-phase study, the study of consciousness, revealing anomalous positive
although behavioural endpoints would not be of primary inter- effects on the complexity of brain activity, the low values of
est, standardized assessments would be incorporated where which have come to define states of impaired consciousness.
this is feasible (i.e. the Coma Recovery Scale-Revised and/or The modern era of responsible scientific experimentation with
Wessex Head Injury Matrix). psychedelics is yielding significant support for their safety
In subsequent analysis, it would be of interest to explore the across a range of conditions. Taken together, we call for an
relationship between pre- and post-dose EEG complexity and open-minded attitude about the possibility of exploring the po-
behavioural measures. Given the evidence that measures de- tential of psychedelics to elevate conscious awareness in
rived from EEG connectivity in patients with DoC could not only patients with DoC.
prognosticate recovery (Sitt et al. 2014; Chennu et al. 2017), but
also predict response to intervention (Thibaut et al. 2018), it is
Authors’ Contributions

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possible that pre-dosage EEG measures could be used in a simi-
lar way in relation to psychedelic treatment. G.S.: conceptualization, drafting of and revision of the manu-
We recommend detailed consideration of the choice and script; R.L.C.-H.: conceptualization and revision of the
setup of the environment and the support provided to the pa- manuscript.
tient during study sessions, although we acknowledge it will be
difficult to know how a DoC patient could be prepared for the
Acknowledgements
expected effects of the drug. The sessions themselves would be
carried out in a familiar environment for the patient, with their We thank Prof Diane Playford, Dr Sophie Duport and the
normal carers present. In our study of treatment-resistant de- staff at the Royal Hospital for Neurodisability (RHN), who
pression, psychological support was provided before, during provided valuable feedback on our proposal in June 2018.
and after each session. There is evidence to suggest that control We also thank Prof Rob Leech, Dr Fernando Rosas, Dr Leor
of context is important for positive therapeutic responses Roseman and Dr Edward Presswood for their comments on
(Carhart-Harris et al. 2018). The timing of dosing in relation to a draft of the manuscript. We are very grateful to the anony-
markers of the circadian rhythm, which is likely to influence mous referees for their comments. G.S. is funded by a
arousal, should also be factored in (Blume et al. 2017). National Institute for Health Research (NIHR) Clinical
In later studies of psilocybin as a treatment for patients with
Lectureship. R.L.C.-H. is funded by the Alex Mosley Trust,
DoC, behavioural indices like the Coma Recovery Scale - Revised
Tim Ferriss, Anton Bilton, the Singhal Health Foundation
(CRS-R) must ultimately be used as the primary outcome mea-
and the Ad Astria Chandaria Foundation.
sure. In this sense, we would wish to treat psilocybin no differ-
ently than any other experimental intervention for DoC. At Conflict of interest statement. G.S. has nothing to report. R.L.C.-
present, we view brain complexity as an informative index of H. is currently advising Compass Pathways, a commercial
conscious content, but for this to be functionally relevant in the initiative to develop psilocybin as a medicine.
context of psychedelic interventions in DoC, it would be vital to
establish that a psychedelic-induced increase in complexity ul-
timately translates into behavioural improvements, with the References
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