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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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DOI: 10.1177/0269881118754710
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
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.
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.
754710JOP0010.1177/0269881118754710Journal of PsychopharmacologyCarhart-Harris et al.
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
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
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
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 ( 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 (; 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.
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, as well as to those
who completed the survey.
1. By ‘psychedelics’, we refer to the classic psychedelics such
as LSD, psilocybin/psilocin and dimethyltryptamine/aya-
huasca, pharmacological definable by serotonin 2A receptor
Robin Lester Carhart-Harris
Aixala M (2017) Psychotherapeutic Intervention in Integration of Difficult
Psychedelic Experiences: The ICEERS Support Service. Oakland, CA:
Psychedelic Science. Available at:
(accessed 20 January 2018).
Albarelli HP (2009) A Terrible Mistake: The Murder of Frank Olson and
the CIA’s Secret Cold War Experiments. Walterville, OR: Trine Day.
Alboni S, van Dijk RM, Poggini S, et al. (2017) Fluoxetine effects on
molecular, cellular and behavioral endophenotypes of depression are
driven by the living environment. Mol Psychiatry 22: 552–561.
Ashby CR Jr, Edwards E and Wang RY (1994) Electrophysiological
evidence for a functional interaction between 5-HT1A and 5-HT2A
receptors in the rat medial prefrontal cortex: An iontophoretic study.
Synapse 17: 173–181.
Austin P, Tudorie V, Stone R, et al. (2017) What is the Third Wave of
Psychedelics? Available at: (accessed
20 January 2018).
Barrett FS, Bradstreet MP, Leoutsakos JS, et al. (2016) The Challenging
Experience Questionnaire: Characterization of challenging experiences
with psilocybin mushrooms. J Psychopharmacol 30: 1279–1295.
Bentall RP (2009) Doctoring the Mind: Is Our Current Treatment of Men-
tal Illness Really any Good? New York: New York University Press.
Branchi I (2011) The double edged sword of neural plasticity: Increasing
serotonin levels leads to both greater vulnerability to depression and
improved capacity to recover. Psychoneuroendocrinology 36: 339–351.
Carbonaro TM, Bradstreet MP, Barrett FS, et al. (2016) Survey study
of challenging experiences after ingesting psilocybin mushrooms:
Acute and enduring positive and negative consequences. J Psycho-
pharmacol 30: 1268–1278.
Carhart-Harris RL, Erritzoe D, Haijen E, et al. (2017) Psychedelics and
connectedness. Psychopharmacology (Berl). Epub ahead of print 10
August 2017. doi: 10.1007/s00213-017-4701-y.
Carhart-Harris RL and Goodwin GM (2017) The therapeutic potential of
psychedelic drugs: Past, present and future. Neuropsychopharmacol-
ogy 42: 2105–2113.
Carhart-Harris RL, Kaelen M, Bolstridge M, et al. (2016) The paradoxi-
cal psychological effects of lysergic acid diethylamide (LSD). Psy-
chol Med 46: 1379–1390.
Carhart-Harris RL, Kaelen M, Whalley MG, et al. (2015) LSD enhances
suggestibility in healthy volunteers. Psychopharmacology (Berl)
232: 785–794.
Carhart-Harris RL, Leech R, Williams TM, et al. (2012) Implications for
psychedelic-assisted psychotherapy: Functional magnetic resonance
imaging study with psilocybin. Br J Psychiatry 200: 238–244.
Carhart-Harris RL and Nutt DJ (2017) Serotonin and brain function: A
tale of two receptors. J Psychopharmacol 31: 1091–1120..
Caspi A, Hariri AR, Holmes A, et al. (2010) Genetic sensitivity to the
environment: The case of the serotonin transporter gene and its
implications for studying complex diseases and traits. Am J Psychia-
try 167: 509–527.
Chiarotti F, Viglione A, Giuliani A, et al. (2017) Citalopram amplifies
the influence of living conditions on mood in depressed patients
enrolled in the STAR*D study. Transl Psychiatry 7: e1066.
Cohen S (1960) Lysergic acid diethylamide: Side effects and complica-
tions. J Nerv
Ment Dis 130: 30–40.
Demyttenaere K (2016) Taking the depressed “person” into account
before moving into personalized or precision medicine. World Psy-
chiatry 15: 236–237.
Dobkin de Rios M (2009) The Psychedelic Journey of Marlene Dobkin
de Rios: 45 Years with Shamans, Ayahuasqueros, and Ethnobota-
nists. Rochester, VT: Park Street Press.
Erritzoe D, Nutt DJ and Carhart-Harris R (2017) Concerns regarding con-
clusions made about LSD-treatments. Hist Psychiatry 28: 257–260.
Erritzoe D and Richards WA (2017) Lessons to be learned from early
psychedelic therapy in Denmark. Nordic journal of psychiatry 71:
Fadiman J (2017) Microdosing: The Phenomenon, Research Results,
and Startling Surprises. Available at:
(accessed 20 January 2018).
Feinberg B (2017) Conflict and Transformation in Mazatec and Outsiders’
Views of the Therapeutic Value of Mushroom Use in Huautla. Avail-
able at: (accessed 20 January 2018).
Garcia-Romeu A, Griffiths RR and Johnson MW (2014) Psilocybin-
occasioned mystical experiences in the treatment of tobacco addic-
tion. Curr Drug Abuse Rev 7: 157–164.
Goodwin GM (2016) Psilocybin: Psychotherapy or drug? J Psychophar-
macol 30: 1201–1202.
Griffiths RR, Johnson MW, Carducci MA, et al. (2016) Psilocybin pro-
duces substantial and sustained decreases in depression and anxiety
in patients with life-threatening cancer: A randomized double-blind
trial. J Psychopharmacol 30: 1181–1197.
Griffiths RR, Johnson MW, Richards WA, et al. (2011) Psilocybin occa-
sioned mystical-type experiences: Immediate and persisting dose-
related effects. Psychopharmacology (Berl) 218: 649–665.
Griffiths RR, Richards WA, McCann U, et al. (2006) Psilocybin can
occasion mystical-type experiences having substantial and sustained
personal meaning and spiritual significance. Psychopharmacology
(Berl) 187: 268–283; discussion 284–292.
Harmer CJ and Cowen PJ (2013) ‘It’s the way that you look at it’–a
cognitive neuropsychological account of SSRI action in depression.
Philos Trans R Soc Lond B Biol Sci 368: 20120407.
Hartogsohn I (2015) The Psycho-Social Construction of LSD: How Set
and Setting Shaped the American Psychedelic Experience 1950–
1970. PhD dissertation. Israel: Bar Ilan University.
Hartogsohn I (2016) Set and setting, psychedelics and the placebo
response: An extra-pharmacological perspective on psychopharma-
cology. J Psychopharmacol 30: 1259–1267.
Carhart-Harris et al. 7
Hartogsohn I (2017) Constructing drug effects: A history of set and set-
ting. Drug Sci Pol Law 3: 2050324516683325.
Hendricks PS, Thorne CB, Clark CB, et al. (2015) Classic psychedelic
use is associated with reduced psychological distress and suicidal-
ity in the United States adult population. J Psychopharmacol 29:
Hofmann A (1980) LSD: My Problem Child. NY: McGraw-Hill.
Jack (2017) Magic Mushrooms Take a Trip into Clinical Trials. https://
(accessed 10 September 2017).
Johansen PØ and Krebs TS (2015) Psychedelics not linked to mental
health problems or suicidal behavior: A population study. J Psycho-
pharmacol 29: 270–279.
Johnson M, Richards W and Griffiths R (2008) Human hallucinogen
research: Guidelines for safety. J Psychopharmacol 22: 603–620.
Jokela M, Keltikangas-Jarvinen L, Kivimaki M, et al. (2007) Serotonin
receptor 2A gene and the influence of childhood maternal nurtur-
ance on adulthood depressive symptoms. Arch Gen Psychiatry 64:
Jokela M, Lehtimaki T and Keltikangas-Jarvinen L (2007a) The influ-
ence of urban/rural residency on depressive symptoms is moderated
by the serotonin receptor 2A gene. Am J Med Genet B Neuropsychi-
atr Genet 144B: 918–922.
Jokela M, Lehtimaki T and Keltikangas-Jarvinen L (2007b) The serotonin
receptor 2A gene moderates the influence of parental socioeconomic
status on adulthood harm avoidance. Behav Genet 37: 567–574.
Kaelen M, Barrett FS, Roseman L, et al. (2015) LSD enhances the emo-
tional response to music. Psychopharmacology (Berl) 232: 3607–
Kaelen MG, Giribaldi B, Raine J, et al. (2018) The hidden therapist: Evi-
dence for a central role of music in psychedelic therapy. Psychophar-
macology (Berl)
Kazdin AE (2007) Mediators and mechanisms of change in psychother-
apy research. Annu Rev Clin Psychol 3: 1–27.
Kirsch I (2013) The placebo effect revisited: Lessons learned to date.
Complement Ther Med 21: 102–104.
Krebs TS and Johansen PØ (2012) Lysergic acid diethylamide (LSD) for
alcoholism: Meta-analysis of randomized controlled trials. J Psycho-
pharmacol 26: 994–1002.
Labate BC (2014) Ayahuasca Shamanism in the Amazon and Beyond.
Oxford, NY: Oxford University Press.
Labate BC and Cavnar C (2016) Peyote: History, Tradition, Politics, and
Conservation. Santa Barbara, CA: Praeger.
Larsen JK (2016) Neurotoxicity and LSD treatment: A follow-up study
of 151 patients in Denmark. Hist Psychiatry 27: 172–189.
Leary T, Litwin GH and Metzner R (1963) Reactions to Psilocybin
Administered in a Supportive Environment. J Nerv Ment Dis 137:
Lee MA and Shlain B (1985) Acid Dreams: The Complete Social History
of LSD, the CIA, the Sixties and Beyond. London: Pan.
Lee MA and Shlain B (1992) Acid Dreams: The Complete Social History of
LSD, the CIA, the Sixties and Beyond. New York: Grove Weidenfeld.
Loizaga-Velder A and Verres R (2014) Therapeutic effects of ritual aya-
huasca use in the treatment of substance dependence–qualitative
results. J Psychoactive Drugs 46: 63–72.
Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. (2014) Do the disso-
ciative side effects of ketamine mediate its antidepressant effects? J
Affect Disord 159: 56–61.
Ludwig A, Levine J, Stark L, et al. (1969) A clinical study of LSD treat-
ment in alcoholism. Am J Psychiatry 126: 59–69.
MacLean KA, Johnson MW and Griffiths RR (2011) Mystical experi-
ences occasioned by the hallucinogen psilocybin lead to increases
in the personality domain of openness. J Psychopharmacol 25:
Maslow AH (1976) Religions, Values and Peak-experiences. Harmond-
sworth: Penguin.
Nettl B (1956) Music in Primitive Culture. [With Musical Illustrations
and a Bibliography.]. Cambridge: Harvard University Press.
Nour MM, Evans L, Nutt D, et al. (2016) Ego-dissolution and psychedel-
ics: Validation of the ego-dissolution inventory (EDI). Front Hum
Neurosci 10: 269.
Novak SJ (1998) Second thoughts on psychedelic drugs. Endeavour 22:
Oram M (2014) Efficacy and enlightenment: LSD psychotherapy and the
Drug Amendments of 1962. J Hist Med Allied Sci 69: 221–250.
Richards WA (2015) Sacred Knowledge: Psychedelics and Religious
Experiences. New York: Columbia University Press.
Roseman L, Nutt DJ and Carhart-Harris RL (2017) Quality of acute psy-
chedelic experience predicts therapeutic efficacy of psilocybin for
treatment-resistant depression. Front Pharmacol 8: 974.
Ross S, Bossis A, Guss J, et al. (2016) Rapid and sustained symptom
reduction following psilocybin treatment for anxiety and depression
in patients with life-threatening cancer: A randomized controlled
trial. J Psychopharmacol 30: 1165–1180.
Rucker JJ, Jelen LA, Flynn S, et al. (2016) Psychedelics in the treatment
of unipolar mood disorders: A systematic review. J Psychopharma-
col 30: 1220–1229.
Schwartz C (2017) Molly at the Marriott: Inside America’s Premier Psy-
chedelics conference. The New York Times. Available at: https://
daily-life.html (accessed 6 May 2017).
Sos P, Klirova M, Novak T, et al. (2013) Relationship of ketamine’s
antidepressant and psychotomimetic effects in unipolar depression.
Neuro Endocrinol Lett 34: 287–293.
Stevens J (1987) Storming Heaven: LSD and the American Dream. New
York: Atlantic Monthly Press.
Studerus E, Gamma A, Kometer M, et al. (2012) Prediction of psilocybin
response in healthy volunteers. PLoS One 7: e30800.
Timmermann C, Spriggs MJ, Kaelen M, et al. (2017) LSD modulates
effective connectivity and neural adaptation mechanisms in an
auditory oddball paradigm. Neuropharmacology. pii: S0028–
Tupper KW and Labate BC (2014) Ayahuasca, psychedelic studies and
health sciences: The politics of knowledge and inquiry into an Ama-
zonian plant brew. Curr Drug Abuse Rev 7: 71–80.
Waldman A (2017) A Really Good Day: How Microdosing Made a Mega
Difference in My Mood, My Marriage, and My Life. New York: Knopf.
Wallace AF (1959) Cultural determinants of response to hallucinatory
experince. AMA Arch Gen Psychiatry 1: 58–69.
Watts R, Day C, Krzanowski J, et al. (2017) Patients’ accounts of
increased “connectedness” and “acceptance” after psilocybin for
treatment-resistant depression. J Humanist Psychol 57: 520–564.
Winkelman M (2005) Drug tourism or spiritual healing? Ayahuasca
seekers in Amazonia. J Psychoactive Drugs 37: 209–218.
Zinberg NE (1984) Drug, Set, and Setting: The Basis for Controlled
Intoxicant Use. New Haven; London: Yale University Press.
... Prevalence does appear to be lower in controlled research studies. Moreover, consistent with long-held assumptions 29 , iatrogenic responses appear to be highly-if not entirely-context dependent 25,30 . ...
... These variables can be categorised into 3 major domains: namely, (1) factors pertaining to the individual's psychological vulnerability (including their young age), (2) (negative) set, setting and/or matrix factors, and (3) factors linked to the substance itself-and most commonly, its (excessively high) dose and particular action. It is worth noting that these factors are entirely consistent with those highlighted in previous work in relation to the hypothesised context-dependency of responses to psychedelics [e.g., see Fig. 2 in 30 ]. ...
... Thus, we are left with an intentionally parsimonious model that emphasizes a key axis of plasticity that is activated dose-dependently by the psychedelic and may involve some individual differences in sensitivity-interacting with a critical second dimension, which refers to the context in which the use occurs. Here, 'context' can be used as an umbrella term to subsume the sub-dimensions of set, setting and matrix [e.g., as was done here 30 ]. Individual sensitivities could be subsumed into both dimensions, where e.g., greater sensitivity to psychedelics would positively interact with their direct pro-plasticity effects but could also be regarded as a 'negative context'e.g., in terms of adverse life experiences or psychological vulnerabilities brought to the experience. ...
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Abstract Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53%
... 12,[16][17][18] Thus, it is hypothesized that alterations in psychological processes resulting from these altered states of consciousness may play a pivotal role in the therapeutic effects of psychedelics. 19,20 Among the most scrutinized altered states of consciousness is the mystical experience. 11,15,21,22 Stace examined reports of mystical experiences across various world religions and identified universal elements independent of religious and cultural contexts. ...
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Introduction Psychedelics have garnered increased attention as potential therapeutic options for various mental illnesses. Previous studies reported that psychedelics cause psychoactive effects through mystical experiences induced by these substances, including an altered state of consciousness. While this phenomenon is commonly assessed by the Mystical Experiences Questionnaire (MEQ30), a Japanese version of the MEQ30 has not been available. The aim of this study was to develop the Japanese version of the MEQ30. Methods We adhered to the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient‐Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation” in our translation process. Two Japanese psychiatrists independently performed forward translations, from which a unified version was derived through reconciliation. This version was subsequently back‐translated into English and reviewed by the original authors for equivalency. The iterative revision process was carried out through ongoing discussions with the original authors until they approved the final back‐translated version. Results The final, approved back‐translated version of the MEQ30 is presented in the accompanying figure. Additionally, the authorized Japanese version of the MEQ30 is included in the Appendix A. Conclusions In this study, we successfully developed a Japanese version of the MEQ30. This scale will facilitate the assessment of mystical experiences associated with psychedelic‐assisted therapy among Japanese speakers. Further research is warranted to evaluate the reliability and validity of this newly translated scale.
... The mindset of the individual consuming a psychedelic substance, as well as the setting in which Frontiers in Psychiatry 07 they consume psychedelics, are reported to have a large impact on the nature of the psychedelic experience (72). This phenomenon is referred to as "set and setting. ...
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Introduction Psilocybin use has been linked to lowered odds of crime-related outcomes across a host of observational studies. No studies have investigated how these associations may differ among those of different races and ethnicities. Methods Using a nationally-representative sample of 734,061 adults from the National Survey on Drug Use and Health (2002–2020), we investigated whether race and ethnicity moderate the associations between lifetime psilocybin use and four measures of crime arrests (property crime, assault, serious violence, and miscellaneous crimes). Results First, we replicated prior findings and demonstrated that psilocybin confers lowered odds of crime arrests for all four outcomes in question. Second, we demonstrated that race and ethnicity moderate the associations between lifetime psilocybin use and crime arrests for three of our four outcomes. Third, we examined the associations between psilocybin and crime arrests across different races and ethnicities (White, Black, Indigenous, Asian, Multiracial, and Hispanic participants). Psilocybin conferred lowered odds of at least one crime arrest outcome for all racial and ethnic groups except for Black and Hispanic participants. Discussion Future investigations should take an intersectional approach to studying the interrelationship of sociodemographic factors, psychedelic use, and crime, examine the structural factors (i.e., systemic racism) that may underlie these results, and investigate whether psychedelics can alleviate mental health disorders that contribute to cycles of recriminalization for communities of color.
... When administered in a controlled environment, adverse effects are less likely to arise and can be mitigated by trained therapists [63,64]. Therefore, two aspects of the clinical trial must be carefully considered: the dose administered and the setting where sessions occur. ...
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Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid diethylamide (LSD) on anxiety-like behaviors in preclinical models, and the clinical literature on anxiolytic effects of LSD in healthy volunteers and patients with ADs. Preclinical and clinical findings show that even if LSD may exacerbate anxiety acutely (both in "microdoses" and "full doses"), it induces long-lasting anxiolytic effects. Only two randomized controlled trials combining LSD and psychotherapy have been performed in patients with ADs with and without life-threatening conditions, showing a good safety profile and persisting decreases in anxiety outcomes. The effect of LSD on anxiety may be mediated by serotonin receptors (5-HT1A/1B, 5-HT2A/2C, and 5-HT7) and/or transporter in brain networks and circuits (default mode network, cortico-striato-thalamo-cortical circuit, and prefrontal cortex-amygdala circuit), involved in the modulation of anxiety. It remains unclear whether LSD can be an efficacious treatment alone or only when combined with psychotherapy, and if "microdosing" may elicit the same sustained anxiolytic effects as the "full doses". Further randomized controlled trials with larger sample size cohorts of patients with ADs are required to clearly define the effective regimens, safety profile, efficacy, and feasibility of LSD for the treatment of ADs.
Psychedelic substances have a long history of use in traditional healing and religious ceremonies worldwide and are increasingly being investigated for their possible therapeutic usage. However, there is still a lack of consensus regarding how best to characterize the psychological effects of psychedelics and how they bring about the positive therapeutic outcomes observed in clinical studies. The aim of this article is to review available evidence from quantitative and qualitative studies on psychedelic-assisted therapy, as well as neurobiological studies, in relation to the hypothesis that psychedelics facilitate the emergence of emotionally charged unconscious material, originally proposed by pioneering psychedelics researcher Stanislav Grof. The reviewed process studies of therapeutic mechanisms in psychedelic-assisted therapy and qualitative studies of treatment participants clearly indicate that the psychedelic experience is associated with the subjective experience of having increased access to and awareness of emotions, memories, and perceptions that are normally avoided or outside of conscious awareness. Brain-imaging studies point to several different neurobiological effects of psychedelics that might be related to these subjective psychological experiences. Available evidence also indicates that this process might constitute an important therapeutic mechanism in psychedelic-assisted therapy, worthy of further investigation.
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Objectives The mindfulness-informed intervention that has so far received the most attention as an adjunct to psychedelic-assisted psychotherapy is Acceptance and Commitment Therapy (ACT), but little remains known about potential synergies between psychedelic-assisted psychotherapy and mindfulness-based interventions such as Mindfulness-Based Cognitive Therapy (MBCT). This paper examines and evaluates the therapeutic compatibility of MBCT with psychedelic-assisted psychotherapy, and their potential synergies. Methods This study represents a narrative review of the current literature on psychedelic-assisted psychotherapy and MBCT. Results We demonstrate how MBCT targets core processes including acceptance, being present, concentration, decentering and embracing difficulties — and outline why strengthening these capacities with systematic meditation training may prove invaluable during the preparation, dosing and integration phases of psychedelic-assisted psychotherapy. Conclusions MBCT’s emphasis on systematic training in mindfulness meditation and fostering nonjudgmental presence aligns well with the states of consciousness induced by psychedelics, highlighting its potential to enhance various stages of both the psychedelic experience and subsequent integration. By equipping individuals with effective mindfulness and cognitive restructuring techniques, MBCT may offer advantages beyond those provided by ACT, such as the ability to skillfully navigate and manage challenging experiences that can emerge during different phases of the psychedelic experience and integration. This suggests that MBCT’s unique approach may complement psychedelic-assisted psychotherapy in ways that ACT may not fully address, particularly in the context of handling challenging experiences.
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Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium–high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose–response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.
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Rationale: Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role. Objectives: The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy. Methods: Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience). Results: Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not. Conclusions: This study indicates that music plays a central therapeutic function in psychedelic therapy.
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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,
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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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Psychedelic drugs are creating ripples in psychiatry as evidence accumulates of their therapeutic potential. An important question remains unresolved however: how are psychedelics effective? We propose that a sense of connectedness is key, provide some preliminary evidence to support this, and suggest a roadmap for testing it further.
Sacred Knowledge is the first well-documented, sophisticated account of the effect of psychedelics on biological processes, human consciousness, and revelatory religious experiences. Based on nearly three decades of legal research with volunteers, William A. Richards argues that, if used responsibly and legally, psychedelics have the potential to assuage suffering and constructively affect the quality of human life. Richards’s analysis contributes to social and political debates over the responsible integration of psychedelic substances into modern society. His book serves as an invaluable resource for readers who, whether spontaneously or with the facilitation of psychedelics, have encountered meaningful, inspiring, or even disturbing states of consciousness and seek clarity about their experiences. Testing the limits of language and conceptual frameworks, Richards makes the most of experiential phenomena that stretch our conception of reality, advancing new frontiers in the study of belief, spiritual awakening, psychiatric treatment, and social well-being. His findings enrich humanities and scientific scholarship, expanding work in philosophy, anthropology, theology, and religious studies and bringing depth to research in mental health, psychotherapy, and psychopharmacology.
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.