Psychedelics and the essential importance of context

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DOI: 10.1177/0269881118754710
Abstract
Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.
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We are currently witnessing a renaissance in psychedelic research;
so much so, that phrases like this are beginning to feel platitudinal.
Some have referred to the present resurgence as a ‘third wave’
(Austin et al. 2017), since this is not the first time psychedelics
have brightened the fields of psychology and psychiatry (Carhart-
Harris and Goodwin, 2017), and certain indigenous cultures – most
notably in the Americas – have celebrated their effects since
ancient times (Labate, 2014; Labate and Cavnar, 2016). Given the
promising nature of the current psychedelic research climate, it
feels sensible to draw attention to potential pitfalls, so as to protect
against them. The main hypothesis of this article is that the thera-
peutic action of psychedelics is fundamentally reliant on context
both in the psychological and environmental sense. It is argued that
neglect of context could render a psychedelic experience not only
clinically ineffective but also potentially harmful – accounting, in
part, for the negative stigma that still shackles these drugs (Erritzoe
et al., 2017; Erritzoe and Richards, 2017).1
Beginning chronologically, ceremonial use of psychedelics
among indigenous people has historically placed, and still contin-
ues to place, great emphasis on environmental context and psy-
chological factors brought to the experience, such as having a
clear intention and an open, enquiring attitude, as well as the
importance of ceremony, ritual, and song (Labate, 2014; Loizaga-
Velder and Verres, 2014; Nettl, 1956; Tupper and Labate, 2014).
Indigenous approaches are often animistic in nature, for example,
ascribing a healing sentience to the relevant psychedelic plant(s),
special powers to the guiding shaman and a locus of therapeutic
action to the chants (icaros) sung to the recipient(s) (Dobkin de
Rios, 2009). Some adherents of the indigenous model consider
neglect of these components disrespectful, and sensitivities exist
regarding the appropriation of indigenous methods by Westerners
(Feinberg, 2017; Schwartz, 2017), although a ready willingness
to adapt to Western preferences can also be seen among certain
indigenous practitioners (Feinberg, 2017; Labate, 2014).
Moving into the 1950–60s and the first period of concerted sci-
entific research on psychedelics, the importance of context was
quickly appreciated. The precise origins of the terms ‘set’ and ‘set-
ting’ are difficult to pin down (Zinberg, 1984), but it is clear that they
were embraced by the 1960s Harvard academic-turned-psychedelic-
popularist Timothy Leary, who used them to refer to the various psy-
chological and environmental influences on a psychedelic drug
experience (Leary et al., 1963); ‘set’ being the expectations, assump-
tions and any other pre-existing psychological factors (including
psychopathology) one brings to an experience and ‘setting’ being the
environmental context in which it occurs (Hartogsohn, 2016; 2017;
Leary et al., 1963). Interestingly, some positive psychological after-
effects were reported after the earliest known use of LSD (Hofmann,
1980), despite ‘set’ and ‘setting’ being largely uncontrolled and the
acute experience being mostly unpleasant. This apparent paradox,
between acutely challenging high-dose psychedelic experiences
Psychedelics and the essential importance
of context
Robin Lester Carhart-Harris1, Leor Roseman1, Eline Haijen1,
David Erritzoe1, Rosalind Watts R1, Igor Branchi2 and Mendel Kaelen1
Abstract
Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this
opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here
under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated
plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive
interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic
experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good
practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these
compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that
can help minimise harms and maximise potential benefits.
Keywords
Psychedelics, psychotherapy, serotonin
1 Psychedelic Research Group, Neuropsychopharmacology Unit, Centre
for Psychiatry, Division of Brain Sciences, Department of Medicine,
Imperial College London, London, UK
2 Center for Behavioral Sciences and Mental Health, Istituto Superiore
di Sanità, Viale Regina Elena, Roma, Italy
Corresponding author:
Robin Lester Carhart-Harris, Psychedelic Research Group,
Neuropsychopharmacology Unit, Centre for Psychiatry, Division of
Brain Sciences, Department of Medicine, Imperial College London,
Burlington Danes Building, Hammersmith Campus, Du Cane Road,
London, W12 0NN, UK.
Email: r.carhart-harris@imperial.ac.uk
754710JOP0010.1177/0269881118754710Journal of PsychopharmacologyCarhart-Harris et al.
research-article2018
Perspectives
2 Journal of Psychopharmacology 00(0)
being associated with longer-term psychological benefits, has been
highlighted and discussed elsewhere (Carhart-Harris et al., 2016;
Carbonaro et al., 2016).
Subsequent therapeutic applications of LSD in the 1950s and
60s did pay special attention to ‘set’ and ‘setting’ however – and
the associated clinical outcomes were accordingly impressive,
with reassuring safety and promising efficacy data (Krebs and
Johansen, 2012; Rucker et al., 2016). Crucially, in cases where
‘set’ and ‘setting’ were intentionally neglected or even manipu-
lated in a negative way, outcomes were considerably less positive
(Albarelli, 2009; Ludwig et al., 1969; Oram, 2014), such as in
military experiments with psychedelics in the 1950s and 60s
(Albarelli, 2009). It is right to acknowledge that cases of wors-
ened mental health after controlled administrations of psyche-
delics have been reported (Larsen, 2016; but see Cohen 1960;
Studerus et al. 2012 for meta-analyses of prevalence data in con-
trolled research, and Hendricks et al., 2015 and Johansen and
Krebs, 2015 for relevant population-level data) and associated
legal cases have been fought and won by plaintiffs (but see
Erritzoe et al., 2017; Erritzoe and Richards, 2017). In the 1950s
and 1960s, rare tragedies linked to psychedelic drug-use (whether
fairly or not) were aggressively exploited by conservative media
and used to manipulate public opinion and justify policy change in
an effective way (Lee and Shlain, 1985). We should be vigilant of
this tactic of misinformation and manipulation, lest it be repeated
in the context of contemporary psychedelic research.
Only when you sensationalize a subject matter do you get a
reform. Without sensationalizing it, you don’t… only when the
press and television come in do you get action. (Senator
Abraham Rubicon in an official meeting on LSD prohibition,
1966, reported in Lee and Shlain, 1985).
Moreover, if the media and associated public opinion were to
turn against psychedelics, as occurred in the mid to late 1960s
(Stevens, 1987), it is logical to suppose that this, in turn, would
impact on expectations, and subsequently experience, in a self-
reinforcing positive feedback loop (Wallace, 1959; Hartogsohn,
2015) (Figure 1). We should be conscious to avoid such a shift in
‘cultural set and setting’ with regards to psychedelics (Hartogsohn,
2015; Wallace, 1959), particularly if is initiated by misinforma-
tion under a political agenda, as occurred in the late 1960s
(Stevens, 1987). Moreover, those considering use of psychedelics
without proper recognition of context should be made aware that
such bad practice could feed into a negative cultural context loop
that could damage the wider therapeutic agenda. Relatedly, it is
important to highlight that while opponents of psychedelics can
manipulate truth for a particular agenda, so can over-zealous pro-
ponents (e.g. see Novak 1998 for a particularly sobering take on
the 1950–60s psychedelic research). Heeding lessons from the
past, those who see value in the therapeutic potential of psyche-
delics might be wise to: (a) not push too hard too soon, and (b) be
vigilant of their own biases.
Returning to the present day, a number of recent trials have
demonstrated promising outcomes with psychologically and
environmentally supported psychedelics sessions for psycho-
logical distress, mood disorders and addiction (Carhart-Harris
and Goodwin, 2017). To our knowledge, all such trials have paid
special attention to context, providing extensive psychological
preparation (often lasting several hours and involving a number
of repeat visits before and after the focal psychedelic experi-
ences) and manipulation of the therapeutic environment, for
example, with low lighting, carefully selected music playlists,
aesthetically pleasing décor and implicit as well as explicit
priming.
Moreover, patients enrolled within modern psychedelic tri-
als typically have access to two compassionate mental health
professionals. These ‘sitters’ or ‘guides’ serve to carefully pre-
pare the patient for their upcoming experience, support them
during it, and help them integrate its content and meaning after-
wards (Johnson et al., 2008; Richards, 2015). Such intensive
support is unusual in the context of conventional mental health-
care services, and despite its questionable feasibility in terms of
time and associated costs, it has been the norm in modern psy-
chedelic trials. In a similar way to how Good Clinical Practice
training ensures a standard of practice in clinical research, spe-
cific training for psychedelic therapy may need to be devel-
oped, standardised and licensed if patient safety is to be
maintained. With large clinical trials of psilocybin for treat-
ment-resistant depression planned in the near future (Jack,
2017), it is reassuring that such matters are currently being
addressed.
We share the view of others (Johnson et al., 2008;
Richards, 2015) that the experiential component of psyche-
delics necessitates and facilitates the development of a
strong therapeutic bond between the patient and his/her
guides. Moreover, although this way of working might ini-
tially challenge overstretched healthcare systems, it could
also afford an opportunity to resurrect the ‘care’ element that
some service-users have found lacking in current mental
Figure 1. A cultural feedback loop that is hypothesised to contribute
to ‘set’ and thus, the nature of an acute psychedelic experience and
its consequent longer-term outcomes. It is proposed that the products
of this cyclical process, that is, acute and longer-term responses to
psychedelics, feed back into cultural context via media reporting which
subsequently affects public opinion, thus influencing the expectations
and preconceptions of individuals who intend to take a psychedelic –
and so perpetuating the process.
Carhart-Harris et al. 3
healthcare practice (Watts, 2017; Bentall, 2009). Therapeutic
alliance is already known to be a major predictor of response
in mental healthcare (Kazdin, 2007) and if the present thesis
is correct, its influence is likely to be greater still in the con-
text of psychedelics (see Carhart-Harris and Nutt, 2017).
Taking stock of these things, it is reasonable to suspect that
‘favourable context’ has contributed significantly to the favourable
outcomes that have been reported in recent clinical trials with
psychedelics. Indirect support for this may be found in the not
inconsiderable (before-versus-after treatment) effects sizes
observed in control conditions in recent double-blind randomised
control trials of psilocybin for end-of-life distress, for example
(Griffiths et al., 2016). It seems unlikely that such effects can be
attributed entirely to conventional ‘positive expectancy’ – the basis
of the standard placebo effect (Kirsch, 2013) – although see
Demyttenaere (2016) and Goodwin (2016) – nor to a low-level
pharmacological effect if presumed-inactive doses of the experi-
mental drug are used as the control (e.g. 1 mg/70 kg for 75% of the
patients in Griffiths et al. 2016). Most likely in our view, is a favour-
able-context effect mediated by positive expectancy and excep-
tional care. This said, if a sufficient active dose of a psychedelic is
given, it seems reasonable to suspect that contextual influences
would be amplified by the plasticity-promoting effects of serotonin
2A receptor signalling (see Carhart-Harris and Nutt, 2017).
Comprehensive approaches to drug action, that properly
acknowledge context, have been gaining traction in psychophar-
macology in recent years, as evidenced by seminal gene × environ-
ment (Caspi et al., 2010), drug × cognition (Harmer and Cowen,
2013), and drug × environment (Alboni et al., 2017) interaction
work. The central argument of the present paper is that at least the
same degree of emphasis needs to be placed on extra-pharmaco-
logical factors in relation to psychedelics – Figure 2 (see Carhart-
Harris and Nutt, 2017). Indeed, in line with recent hypotheses
(Branchi, 2011; Carhart-Harris and Nutt, 2017) and findings
(Chiarotti et al., 2017), it is proposed that the pro-plasticity effects
of serotonin (Branchi, 2011) – and serotonin 2A receptor agonism
particularly (Carhart-Harris and Nutt, 2017; Jokela et al., 2007;
Jokela et al., 2007a, Jokela et al., 2007b) – renders the psychedelic
experience exceptionally sensitive to context. Insufficient appre-
ciation of this principle may lead to risky and potentially harmful
applications of psychedelics – which could jeopardise the healthy
progress of psychedelic research – as well as the mental health of
anyone who misuses these drugs (Oram, 2014).
Remarkably, despite its widespread adoption among psyche-
delic researchers, few controlled studies have ever been per-
formed to test the assumed relationship between psychedelics
and context (although see Ludwig et al., 1969). In terms of our
own research, the closest we have come to testing this has been
to investigate the influence of music (Kaelen et al., 2015;
Kaelen, 2018), positive autobiographical memory scripts
(Carhart-Harris et al., 2012) and creative imagery/suggestibility
on the psychedelic experience (Carhart-Harris et al., 2015), and
in all cases we have found an enhanced influence in the drug
condition versus placebo. Moreover, we have also found that
patients’ relationship to the music they listen to during psilocy-
bin therapy sessions is predictive of the quality of their experi-
ence, which in turn is predictive of long-term therapeutic
outcomes (Kaelen et al., 2017).
It is logical to infer from such findings that psychedelics’
specific pharmacology works synergistically with context, creat-
ing a certain kind of experience that is conducive to particular
outcomes (Carhart-Harris and Nutt, 2017; Garcia-Romeu et al.,
2014; Griffiths et al., 2016; MacLean et al., 2011; Roseman
et al., 2017; Ross et al., 2016). Increased serotonin 2A receptor
signalling mediating cortical plasticity and an associated sensi-
tivity to internal (i.e. endogenous processes and pre-existing
mental context) and external influence (i.e. the environment), is
proposed to be the key underlying mechanism (Carhart-Harris
and Nutt, 2017). It is interesting to consider whether the impact
of a given contextual factor is dependent on the level at which it
captures and resonates with an individual’s underlying emo-
tional and cognitive state (Kaelen et al., 2017). Relatedly, we
have often observed that participants are relatively insensitive to
conventional task-based stimuli under psychedelics, as the rele-
vant stimuli fail to engage their attention and/or interest (see
Timmermann et al., 2017 for a relevant discussion).
Looking to the future, it seems vital that new studies be
conducted to test the hypothesised primacy of context in shap-
ing the nature of a psychedelic experience, so as to mitigate
risks and foster the development of optimal treatment
approaches. It is arguably already well established that the
quality of an acute psychedelic experience is predictive of its
longer-term effects (Roseman et al., 2017), and on this basis,
the quest for a non-psychedelic but still therapeutically effec-
tive serotonin 2A receptor agonist may eventually, in our view,
hit a dead end. Indeed, a similar principle may apply in the
context of ketamine for depression research and the search for
non-psychoactive NMDA receptor modulators with therapeu-
tic efficacy equivalent to that of ketamine (Luckenbaugh et al.,
2014; Sos et al., 2013). In our view, a proper acknowledgement
of the importance of context and experience would represent a
positive paradigm shift in pharmacological care in psychiatry.
Previous work has shown that the dose of a psychedelic is
a reliable predictor of the nature of the subsequent psycho-
logical response (Griffiths et al., 2011; Nour et al., 2016;
Studerus et al., 2012). There is also evidence that spatially
confined neuroimaging settings can increase the likelihood of
challenging experiences with psychedelics (Studerus et al.
2012). This is something we have witnessed on at least two
occasions (in approximately 100 psychedelic scan sessions)
with magnetic resonance imaging and magnetoencephalogra-
phy separately – although in retrospect, both cases of transient
anxiety may have been as much to do with negative ‘set’ as the
Figure 2. Extra-pharmacological model of drug action that takes into
account salient contextual factors – see (Carhart-Harris and Nutt,
2017) for discussion. This model is complementary to the cultural
feedback loop model shown in Figure 1. Note: the term ‘pre-state’ is
interchangeable with ‘set’.
4 Journal of Psychopharmacology 00(0)
imaging setting itself. Where feasible, future psychedelic
imaging studies may consider improvements to the imaging
setting through the inclusion of music, the recruitment of
scanner-experienced participants and opportunities for better
pre-session briefing and post-session psychological integra-
tion, as is default in most (if not all) recent and current clinical
trials.
Other than the aforementioned dose-response study (Griffiths
et al. 2011) and retrospective analyses (e.g. Studerus et al. 2012),
controlled studies designed to isolate and test key contextual
variables assumed to influence the quality of a psychedelic expe-
rience have not yet been carried out (but see Ludwig et al. 1969).
It is likely that this is due to the practical and ethical challenges
raised by providing a sub-optimal (let-alone negative or adverse)
context for a full-dose psychedelic experience (Oram, 2014).
One way to resolve this matter may be to design a study involv-
ing low doses of a psychedelic, in which the provision of a sub-
optimal context is feasible.
As touched on briefly above, there has been an emerging
interest in so-called psychedelic ‘microdosing’ in recent years, a
practice of ingesting sub-threshold-to-threshold psychoactive
doses of a psychedelic 2–3 times per week for a given number of
weeks while the ‘user’ goes about their normal life (Fadiman,
2017; Waldman, 2017). While there is as yet no published peer-
reviewed scientific evidence to support the safety and efficacy of
this practice, enthusiastic claims have been made about its impact
on mood, well-being and creative thinking (Fadiman, 2017;
Waldman, 2017).
One alleged merit of microdosing (over ‘full-dosing’) is that
context may be less influential. While this assumption may turn
out to be reliable, there are valid pharmacological reasons to
believe that context may still be important, even with regards to
microdosing (Carhart-Harris and Nutt, 2017). A controlled study
designed to test this would add value, not just in terms of provid-
ing a timely examination of the current claims about microdos-
ing, but also by testing the potentially important association
between serotonin 2A receptor signalling and sensitivity to con-
text (Carhart-Harris and Nutt, 2017). Back-translation involving
comparable environmental (Alboni et al., 2017) and more selec-
tive pharmacological manipulations (Ashby et al., 1994) in non-
human animals could serve to sharpen inferences on any positive
findings from human research.
The number of factors impinging on a psychedelic experience
may be vast. Thus, endeavouring to test them all independently
and in combination is a huge challenge. Initially, we propose test-
ing those elements about which we hold particularly strong prior
hypotheses (e.g., that music and psychotherapy are critical com-
ponents of the treatment model) but there may also be another,
supplementary approach.
Psychedelics are an anomaly among drugs of ‘potential mis-
use’ (Hendricks et al., 2015), not least because those who wish to
have a psychedelic experience often plan ahead for it, sometimes
travelling vast distances to specific retreat centres to receive a
given psychedelic in a particular context (Winkelman, 2005).
Exploiting this phenomenon, we recently set up a web-based sur-
vey system (psychedelicsurvey.com) in which individuals who
plan to take a psychedelic can enter the date of their planned
experience and then receive specific surveys at strategic time
points: (a) 1 week before, (b) 1 day before, (c) 1 day after, and
then (d) 2 weeks after the focal experience. In this way we sought
to test the process of change related to a psychedelic experience,
assessing a large number of potentially salient factors and their
relevant contributions to acute and longer-term outcomes in a
large sample.
Preliminary results from this project can be seen in Figure 3
(see a forthcoming publication for a more complete account of
this study’s methods and results). In model 1, it can be seen that:
(a) feeling ready to ‘surrender to the experience, (b) having a
clear intention for it, (c) having the experience in a therapeutic
setting, and (d) taking a higher dose, are all predictive of having
a certain kind of psychedelic experience which we label ‘peak’
– an intentionally secular term inspired by Abraham Maslow’s
work (Maslow, 1976) – that can effectively be viewed as a syn-
onymous with the concept of a ‘mystical’ experience (Griffiths
et al., 2006; Richards, 2015). Conversely, model 2 reveals that
the same factors – plus being in the company of well-trusted indi-
viduals – protect against a ‘challenging’ psychological experi-
ence (what some might refer to, perhaps too crudely, as a ‘bad
trip’). Consistent with previous work (Griffiths et al., 2016;
Roseman et al., 2017; Ross et al., 2016), we found that having a
peak experience is predictive of improvements in psychological
well-being 2 weeks after the experience (model 1), whereas hav-
ing a challenging experience predicts a deflation of this effect on
well-being (model 2). While higher doses do not strongly predict
challenging experience in this sample, it seems sensible to
assume that biases exist within it (such as extensive prior experi-
ence with and positive attitudes towards psychedelics), and other
studies have suggested that exceeding an optimal dose for peak
experiences (e.g., approximately 25–30 mg psilocybin) may risk
inflating challenging aspects without adding any appreciable
gain in terms of therapeutic benefit (Griffiths et al. 2011).
Briefly, based on additional measures included in this pro-
ject, we are presently working towards resolving putative incon-
sistencies between our data and previous findings. More
specifically, whereas we saw a trend relationship between chal-
lenging experience under a psychedelic and less of an increase
in psychological well-being 2 weeks later, others have found
evidence that challenging experiences can be therapeutically
beneficial (Barrett et al., 2016; Carbonaro et al., 2016).
Potentially resolving this discrepancy, we believe that challeng-
ing experiences can indeed be therapeutically beneficial but only
if personal insight and/or an emotional catharsis follows the rel-
evant experience(s) of psychological struggle. To test this
assumption, we are presently developing an ‘emotional break-
through’ measure, which was applied in the presently described
survey project to good effect. It is also worth noting that previ-
ous studies supporting the therapeutic potential of challenging
experiences required that participants focus on their most chal-
lenging psychedelic experience. Moreover, the ‘long-term’ out-
comes shown in Figure 4 are based on reports 2 weeks post
experience; it seems reasonable to suppose that therapeutically
valuable processes of psychological integration can take longer
than 2 weeks to resolve after a particularly challenging psyche-
delic experience (Aixala, 2017).
In summary, this article has sought to highlight the essential
importance of context in determining the quality of a psychedelic
experience and its longer-term outcomes. It is proposed that
neglect of this essential component of the psychedelic treatment
model may account for the rare cases of psychological harm that
have been reported in association with psychedelic use (Larsen,
2016) which have (disproportionately) contributed to their his-
torical negative stigma (Lee and Shlain, 1992). The more
Carhart-Harris et al. 5
optimistic and progressive counterpart to this, however, is that a
careful and honest management of context may serve to mini-
mise harm and maximise the considerable therapeutic potential
of psychedelics (Carhart-Harris and Goodwin, 2017; Carhart-
Harris and Nutt, 2017), yielding a powerful treatment model with
a compelling neuropsychological action that could potentially
benefit a broad cross-section of the populace (Carhart-Harris
et al., 2017; Carhart-Harris and Nutt, 2017).
The future success of psychedelic medicine will depend much
on how scientists, clinicians, investors and policy makers receive
this complex, composite and paradigm-challenging treatment
model. Our view is that greater utilisation of drug × context syn-
ergies may form part of an important paradigm shift in psychiat-
ric care. Another view, however, is that factoring in context is
problematic, since it (over)complicates traditional pharmacologi-
cal models by adding extra psychological variability and practi-
cal and financial burdens related to delivery of care and associated
costs. In response to this, it could be fairly argued that the notion
that the efficacy of traditional pharmacotherapies is exempt from
context is flawed (Alboni et al., 2017; Branchi, 2011) and that the
psychedelic treatment model, while costlier in terms of delivery,
may actually be cost-saving in terms of therapeutic action
(Carhart-Harris et al., 2017; Watts et al., 2017) due to the poten-
tial long-term duration of clinical response after just a small num-
ber of treatment sessions (Carhart-Harris and Goodwin, 2017).
Figure 3. Predicting a trip: Two models based on data derived from web-based survey in 266 participants who completed surveys at four key time points:
(a) 1 week before; (b) 1 day before; (c) 1 day after; and (d) 2 weeks after a specific psychedelic experience. The top model shows factors predicting a ‘peak’ or
‘mystical-type’ experience under a psychedelic, which subsequently predicts improvements in psychological well-being 2 weeks later. The bottom model shows
factors which (if lacking) predict a challenging psychological experience under a psychedelic, which subsequently predicts a reduced increase in psychological
well-being 2 weeks later. Arrows with full lines represent significant relationships between factors and broken lines are used for trend-level relationships.
Readiness contains four items such as ‘I feel ready to surrender to whatever will be’ and ‘I feel open to the upcoming experience’; intention contains two
items, namely: ‘I have a clear intention for the upcoming experience’ and ‘I have strong expectations for the upcoming experience’; trust contains two items,
namely: ‘I have a good feeling about my relationship with the group/people who will be with me during my experience’ and ‘I have a good relationship with
the main person/people who will look after me during the upcoming experience’. This study will be reported more fully in forthcoming publications.
Figure 4. Proposed 2×2 model to test the hypothesised positive interaction
between a psychedelic and an enriched context (condition 1, C1). As
throughout this paper, the term ‘context’ is used generically but could refer
more specifically to either environmental or psychological enrichment versus
an un-enriched or even adverse context (Branchi, 2011). For example,
controlled studies could be designed to test: music versus no music or
low lighting versus standard bright lighting (environmental context); or
psychotherapy versus no-psychotherapy, or priming versus no-priming
(psychological context). We propose that the implementation of such designs
would be safest and most feasible if the dose of the relevant psychedelic is
kept low, so as to mitigate potential risks associated with condition 2 (C2).
Repeat (low) dosing could be implemented as per a classic microdosing
model (https://thethirdwave.com; Fadiman, 2017; Waldman, 2017). With
regards cultural context (see Figure 1.), one might even consider a cross-
cultural study in which key outcomes are compared in a culture where
psychedelic use is legal and celebrated (e.g. in Amazonian regions) versus
one in which it is illegal and stigmatised (e.g. in Western countries).
6 Journal of Psychopharmacology 00(0)
For the sake of science and healthcare over politics, we must
hope that the future be allowed to properly test and tell.
Authors’ contributions
This article was written by RCH. All authors read, commented on and
approved the final manuscript.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: RCH is supported
by the Alex Mosley Charitable Trust and has served as an advisor for
Compass Pathways. We are grateful to Kenneth Jonck and Nicolai Lassen
for their work in relation to Psychedelicsurvey.com, as well as to those
who completed the survey.
Note
1. By ‘psychedelics’, we refer to the classic psychedelics such
as LSD, psilocybin/psilocin and dimethyltryptamine/aya-
huasca, pharmacological definable by serotonin 2A receptor
agonism.
ORCID iD
Robin Lester Carhart-Harris https://orcid.org/0000-0002-6062-7150
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    Introduction: It is a basic principle of the “psychedelic” treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value. Materials and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-Time and DED-by-Time interactions were the primary outcomes of interest. Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson's correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05). Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety. Trial Registration: ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797
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    Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural 'surprise' response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness - suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened 'level' of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.
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    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
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    Objective: To identify patients’ perceptions of the value of psilocybin as a treatment for depression. Method: Twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. Thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. Results: Two main change processes were identified in relation to the treatment. The first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. A third theme concerned comparison between psilocybin and conventional treatments. Patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. Conclusions: These results suggest that psilocybin treatment for depression may work via paradigmatically novel means, antithetical to antidepressant medications, and some short-term talking therapies.
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    Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
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    Selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressant drugs, have a variable and incomplete efficacy. In order to better understand SSRI action, we explored the hypothesis that SSRIs do not affect mood per se but amplify the influence of the living conditions on mood. To this aim, we exploited the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) data set, selected a subpopulation of 591 patients with an overlapping clinical history and analyzed treatment outcome according to dosage −20 or 40 mg per day of citalopram. We found that sociodemographic characteristics affected treatment response in the same direction in the two dose groups, but these effects reached statistical significance only in the 40 mg per day dose group. In the latter, higher improvement rate was associated with having a working employment status (P=0.0219), longer education (P=0.0053), high income (P=0.01) or a private insurance (P=0.0031), and the higher remission rate was associated with having a working employment status (P=0.0326) or longer education (P=0.0484). Moreover, the magnitude of the effect of the sociodemographic characteristics on mood, measured as the percent of patients showing a positive outcome when exposed to favorable living conditions, was much greater—up to 37-fold—in the 40 compared to the 20 mg per day dose group. Overall, our results indicate that citalopram amplifies the influence of the living conditions on mood in a dose-dependent manner. These findings provide a potential explanation for the variable efficacy of SSRIs and might lead to the development of personalized strategies aimed at enhancing their efficacy.
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    This book discusses how Amerindian epistemology and ontology, related to certain indigenous shamanic rituals of the Amazon, spread to Western societies, and how indigenous, mestizo, and cosmopolitan cultures have dialogued with and transformed these forest traditions. Special attention is given to the hallucinogenic brew ayahuasca. Chapters reflect on how displaced indigenous people and rubber tappers are engaged in creative reinvention of rituals, and how these rituals help build ethnic alliances and cultural and political strategies for their marginalized position. The expansion of ayahuasca beyond its Amazonian origin instigated a variety of legal and cultural responses in diverse countries. The chapters address some of the ways these responses have influenced ritual design and performance in traditional and nontraditional contexts. The book also explores modernity’s fascination with “tradition” and the “other.” This phenomenon is directly tied to important contemporary issues in anthropology, such as the relationship between the development of ecotourism and ethnic tourism, recent indigenous cultural revivals, and the emergence of new ethnic identities. Another focus is on trends in the commodification of indigenous cultures in postcolonial contexts, and the combination of shamanism with a network of health and spiritually related services. The collection also addresses the topic of identity hybridization in global societies. It is hoped that this work will add to the understanding of the role of ritual in mediating the encounter between indigenous traditions and modern societies.