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Employing Synergistic Interactions of Virtual Reality and Psychedelics in Neuropsychopharmacology

Employing Synergistic Interactions of Virtual Reality and Psychedelics in
Matthew Moroz*
University of Nevada, Reno
Robin L. Carhart-Harris
Imperial College London
The increased prevalence of various psychiatric disorders continue
to concern [54, 71, 96]. Promising results are starting to emerge
from recent experimental interventions employing VR [32,81], and
psychedelics [14, 69] individually. We propose that for certain
pathologies researchers need not bother themselves as to which
medium offers greater hope. Instead, we hypothesize that the most
effective interventions shall necessarily come from a composite
approach utilizing both.
Traditional medicine adopts similar such synergistic strategies.
Combining codeine and acetaminophen increases the analgesic ef-
fect. While research into the therapeutic effects of novel interven-
tions using VR and psychedelics, independent of one another, is
still in its infancy, we believe that the increased utility of a dual
approach justifies closer examination without delay. We posit three
main benefits from this integrated intervention. Increases in the
efficacy of each individual paradigm due to synergistic coupling,
and increases in specificity due to the ability to tailor bespoke ther-
apies for particular individuals and groups, are achieved directly.
Such increases in efficacy consequently lead to the third benefit of
allowing a therapeutic effect to be achieved while using lower doses
of a given psychedelic compound [19].
Index Terms:
Human-centered computing—Human computer
interaction (HCI)—Interaction paradigms—Virtual reality; Applied
computing—Law, social and behavioral sciences—Psychology
The dawn of highly immersive virtual reality (VR) has coincided
somewhat with a renewed acceptance of psychedelic medicine re-
search [94]. While VR promised much as far back as the 1980s,
psychedelic medicine offered similar promise in the 1950s and 1960s.
The labeling of lysergic acid diethylamide (LSD) and others as
“drugs of abuse” all but put an end to exploration into psychedelics
as possible alternative therapeutic choices. Some 50 or so years later
we see the use of psychedelics in medicine gradually shrugging off
the burden of taboo.
Compounds such as psilocybin, LSD, ketamine, and MDMA offer
renewed hope for those suffering from various psychiatric disorders
including treatment-resistant depression, anxiety, post-traumatic
stress disorder (PTSD), and addiction. The ability of VR to hijack
the human sensorimotor system creates a similar novel therapeutic
potential for applications in mental health. Among the pathologies
put forth as ideal candidates for VR applications are those very same
psychiatric disorders best suited to psychedelic medicine.
Rather than deciding which novel intervention holds the greatest
potential for treatment, we advance a theory that in many cases an
optimum solution necessarily incorporates both techniques. VR is
at its most useful when immersion, and consequently, the user’s
sense of presence, is maximized. This psychological perception
of ‘being in’ the virtual environment (VE) [82] can be increased
by employing psychedelics due to their inherent ability to heighten
suggestibility [11, 88]. The benefits of such mediation are two-fold.
While an elevation of presence is our primary goal, we may also
imagine increased usefulness of virtual avatars due to a leveling out
of the uncanny valley [17,61, 87].
As with VR, environmental setting and sensory stimuli are every-
thing [46, 89]. Minor changes in stimulus may profoundly alter a
users experience. Psychedelic treatments tend to take place within
extremely controlled environments. A sterile medical laboratory
setting provides the necessary safety required when employing such
compounds. Composite treatment solutions employing VR afford
similar control of surroundings while adding far greater opportuni-
ties to evoke specific cognitive and emotional responses [22].
The ability of psychedelics to increase presence, and the ability
of VR to provide controlled sensory stimuli creates the potential for
powerful bespoke treatment solutions. The individual interventions
not only complement each other but offer synergistic interactions
whereby each increases the efficacy of the other. Although ‘ab-
sorption’ (openness to absorbing and self-altering experiences) [93]
initially seems like a synonym for ‘presence’, they are not only differ-
ent but research has shown no significant correlation [67]. We may
argue that a composite intervention involving VR and psychedelics
has the potential to take patients beyond the usual sense of VR
presence and into the realm of absorption resulting in even greater
susceptibility [93].
Current upward trends in prevalence for various psychiatric disor-
ders [4, 21, 54, 71,96] are of great concern. Speculation continues as
to the underlying causes of these shifts while many posit the effects
of modern life [20, 37]. This position comes in different forms
such as increased social isolation and loneliness [50, 65], sedentary
lifestyles [25, 59], distractions of modern technologies [30, 31, 49],
and over prescription [97]. The prevalence of depression in the
U.S. increased from 6.6% to 7.3% from 2005 to 2015. Even more
worrying is the 8.7% to 12.7% change among 12 to 17 year olds [96].
Whatever the factors influencing such swings might be, we must
explore all therapeutic solutions, however novel, which offer hope
to those individuals and communities increasingly impacted.
Technology is finally at a level at which fully immersive VR sim-
ulations are possible. Successful evocation of immersion and the
resulting sense of presence is ultimately dependent upon the incom-
ing sensory stimuli. Visual, auditory, haptic, proprioceptive, and
motor cues in the form of efference copy, should closely match
expectations within the brain. When VR delivers with the neces-
sary fidelity the opportunity for sensory hijack and immersion is
maximized [43].
Incoming sensory stimuli possess an equivalent capacity to make
or break a user’s psychedelic experience. Switching out Black
Sabbath’s ’Paranoid’, for The Orb’s ’Slug Dub’ may go much further
than effecting the enjoyment of the soundtrack which accompanies
their trip. Visual perception, mood, and indeed the character of the
entire experience may be fundamentally altered for the better or
worse depending solely on audition [47, 48, 89].
In defining VR as a technology which provides a space in
which immersive VEs are increasingly possible, we may describe
psychedelics as a catalyst which enhances sensitivity to this space.
Evolution of interactive technologies shall further boost immersion
and presence [63]. What technology lacks, however, is the ability to
directly suppress the brain’s natural reality-testing circuits [5,40, 44].
These circuits, which ordinarily serve to protect against immer-
sion, are desensitized by psychedelics. We may, therefore, label
psychedelics “pro-immersion” compounds able to increase the effi-
cacy of VR as a tool for good.
This increase in efficacy runs both ways. Treatments employing
psychedelics to reduce symptoms in the psychiatric disorders previ-
ously described have shown promising results. Treatments of this
nature tend to be restricted by location and setting due to concerns of
safety. The potency of such interventions may be improved for cer-
tain individuals using VR. The addition of VR simulations tailored
for a given pathology leads to no reduction in safety or control. We
maintain the physical setting of sterile medical laboratory together
with an accompanying psychiatrist/psychotherapist. The real world
set-up shall remain almost unchanged. By donning head mounted
displays, however, the patient may by taken to a far more effective
VE, and the therapist may join when necessary in the form of an
A carefully constructed VR simulation enables us to strategically
guide the experience. In a similar way that music therapy may
be applied in order to induce immersive experiences [80] we may
strategically employ VR in order to evoke a specific cognitive re-
sponse. By targeting a given pathology in this way we may attempt
to alter perception in a precisely defined way. Current psychedelic
treatments delivered in a laboratory together with a mental health
professional have a non-trivial probability of evoking additional
anxiety due to increased feelings of self-consciousness. Immersing
a patient in VR helps mitigate the effect by decreasingly the overtly
clinical nature of their surroundings [64], and therefore enabling the
patient’s experience to develop in a more consistently positive way.
The improvements already described offer extra optimism for the
success of these promising novel treatment paradigms. Certain
psychiatric disorders may not require specific sensory stimulation.
Psychedelics alone may be enough to break a patient out of a spiral
of delusional or negative thoughts/behaviors. However, it is in those
pathologies most benefiting from specific sensory stimulation and
maximal immersion which we focus on. In such cases the synergistic
fusion of VR and psychedelics offers an optimal therapeutic solution
for breaking the delusion and evoking a psychological ‘reset’ [15].
Phobias can have a debilitating impact on the lives of sufferers [42,
78]. Body dismorphic disorder (BDD) holds a similar power to
cause extreme psychological distress [38, 74]. Both conditions offer
difficulties in daily functioning by focusing the sufferer in on a
specific anxiety inducing delusion [75, 76, 86]. It is the very fact
that the misappraisal relates to something concrete which advances
these conditions as prime candidates for the prescribed composite
intervention. Knowledge regarding the offending misconception
allows us to target it directly.
Thus far we have discussed VR and psychedelics in very general
terms. However, it is in the increased efficacy from specificity (analo-
gous to the improvements in therapeutic selectivity from synergistic
drug combinations) [57], which offers such hope for our candidate
Current research demonstrates promising results from the use of
different classes of psychedelics. Serotonergic psychedelics such
Figure 1: Synergistic interactions of composite VR and psychedelics
based therapeutic solutions.
as psilocybin have shown to reduce depressive symptoms and anxi-
ety [12, 13, 83], as have dissociatives such at ketamine [6, 41, 68, 79].
Empathogen-entactogens such as MDMA have shown similar im-
provements for sufferers of PTSD [8,16, 66,70].
Specific classes of psychedelics show greater potential as solu-
tions for specific classes of psychiatric disorder. Certain compounds
may instead prove extremely counterproductive if utilized for the
wrong condition. We have some flexibility regarding which com-
pound within a class, might suit a certain individual, and the level of
dosage. Combining with VR greatly increases our possible interven-
tions. As with psychedelics, specific types of VR simulation shall
naturally fit some disorders better than others.
In treating PTSD we expose patients to a VE which closely mim-
ics the trigger situation of their condition. Combat veterans are taken
virtually back to Vietnam, Afghanistan or Iraq [62,85]. Survivors of
the terrorist attacks of September 11, 2001 [23, 24] relive jets flying
into the World Trade Center and the ensuing aftermath.
Composite interventions of similar specificity can offer hope to
those otherwise unresponsive to treatment. Psilocybin only treat-
ments have already been shown to reduce symptoms in those with
treatment-resistant depression [15, 84, 95, 100]. Providing a tailored
sensory stimulus in order to guide the experience grants both pos-
sible symptom reduction in those still resistant to treatment, and
a potential temporal improvement in symptom reduction for all
patients. One such utility offering VE would include elements of
mindfulness meditation which displays potential as a therapeutic
solution in its own right.
Vipassana (mindfulness) meditation shows similar promise as a
therapeutic solution for alcohol and substance abuse [60], anxiety
and depression [1, 2, 26,52, 53], and stress [91]. For a given individ-
ual we may decide the most effective VE should include a virtual
one-to-one session with an expert Vipassana teacher, or shared group
session. Such a scenario might prove impossible for a patient in the
real world. As part of their bespoke treatment they can instead expe-
rience the meditation practice in a heightened state of suggestibility,
while enjoying the removal of any potentially counterproductive
social anxiety.
Such an intervention may include a pre-rendered VE featuring
a real-world Vipassana teacher such as Matthieu Ricard or Joseph
Goldstein. Alternatively, depending on the patient, we may decide
that a perfectly designed digital avatar exuding the same level of
calm, enlightened, reassuring presence would be preferable. In
either scenario we likely evoke a mystical-type experience in a
patient. Such quality of experience potentially facilitates yet further
long-term improvements in mental health [33,34, 58, 84]. Beneficial
mystical/spiritual experiences of this type are of course possible with
psychedics alone [33, 35]. Guiding in this way, however, increases
the reliability of inducing such experiences [10].
Figure 2: Vir tual environment flexibility enables absolute specificity
when tailoring bespoke therapeutic interventions.
Our candidate pathologies call for absolute specificity of VR sim-
ulation. Virtual reality exposure therapy (VRET) is well-established.
The technique has already been used extensively and has consis-
tently shown promising results when applied to phobias such as
agoraphobia, acrophobia, vehophobia, claustrophobia, aviophobia,
social phobia, and arachnophobia [72, 73]. Although this alternative
to traditional exposure therapy methods has shown to be somewhat
useful, the importance of maximizing immersion and presence has
been identified as key [9,39, 51].
Previous combined approaches to social phobia have included
supplementing exposure therapy with the selective serontonin re-
uptake inhibitor (SSRI) sertraline. While the combination showed
improved efficacy [7, 36], it also evoked adverse effects such as
nausea, malaise, and sexual dysfunction during the study [7], and
significant deterioration in self reported health 28 weeks after cessa-
tion of the treatment [36].
Psilocybin offers far more promise as a potential partner to VRET.
Unlike psilocybin, SSRIs such as sertraline are not direct 5-HT
receptor agonists and so offer none of the associated benefits such as
improved cognitive flexibility, associative learning, and cortical neu-
ral plasticity [13]. These characteristics directly assist in a patient’s
reappraisal of their deluded belief. By allowing the unlearning and
replacement of inaccurate perspectives, with new less exaggerated
versions, a patient is able to break free of their pathology.
These same traits enable an openness to fresh perspectives for
those suffering from BDD. VR simulations might take a number of
different guises and shall depend on the individual patient. In general,
the benefit lies in the ability to provide patients with solid, therapist-
independent information about the misguided mental representation
of their body image [27]. One possible simulation could see a patient
inhabit a number of different avatars in a given VE. With the freedom
to inspect themselves by looking down or in a virtual mirror in a
variety of different virtual bodies (including a virtual version of
their own), we encourage a realization as to the erroneous nature
of their concerns. Additional therapeutic simulations may look to
harness the Proteus effect which has already shown an ability to alter
perception and behavior in VR users inhabiting avatars dissimilar to
their own self [98,99] .
BDD has been associated with incidences of abnormal connec-
tivity in the brain [3,28]. Although the primary aim of employing
a composite psychedelics/VR intervention to BDD sufferers would
be to evoke a perceptual change, we may additionally speculate a
possible mitigation of the effects of such abnormalities. Psychedelic
experience with compounds such as psilcybin and LSD not only in-
crease cortical neural plasticity, but also evoke changes in functional
connectivity [47, 55, 92].
We must consider the infancy of the research which we discuss and
look to combine. A great deal remains to be completely established
and replicated scientifically and so we may be accused of multiplying
this uncertainty by bringing together two, as yet, unestablished
paradigms. When contemplating such arguments we must consider
the restrictions previously, and indeed currently, put upon such
research. Processing power has hindered the emergence of VR
while bureaucracy has done the same for psychedelic medicine.
Despite these obstacles we still see a growing literature of promising
Such is the potential power of combining VR and psychedelics
that we may cause concern by promoting this pairing of interventions.
Only by careful experimentation shall we truly know the effects of
this composite therapeutic treatment. We propose a non-linear sum-
mation relating to treatment benefits but it is difficult to accurately
predict. Perhaps something is lost in the combination which is not
currently obvious to us. Such concerns shall be mitigated by re-
stricting dosage of psychedelic compounds. This restriction shall
lie significantly below the levels currently used and detailed in the
accepted safety guide [45]. We implement such restriction not only
for safety reasons, but to facilitate immersion and presence in the
prescribed VE rather than one generated in the patient’s own mind.
Consequently, we shall hope to experience increased acceptance
from internal review boards when evaluating the research.
In order to maintain absolute safety we shall necessarily accom-
pany the patient with a psychiatrist or psychotherapist with whom
they are completely comfortable. In order to reduce instances of a
patient breaking presence by removing the head mounted display,
we shall introduce the therapist virtually as necessary using social
VR or similar.
One might argue that taking a patient out of the sterile medical
laboratory setting, and into a VE, risks a decrease of expectation and
subsequent loss of any associated placebo effect. We counter such
concerns by emphasizing the complexity of conducting safe inter-
ventions using psychedelics, which in turn may increase expectation.
Additionally, when conducting research with psychedelics we must
concern ourselves that an overly clinical environment, exhibiting
extraneous medical equipment and personnel in white lab coats, may
increase anxious reactions [90].
We propose a novel combined therapeutic approach for a wide range
of psychiatric disorders including depression, anxiety, PTSD, and
addiction. We encourage others to explore the usefulness of this
technique for such disorders while we focus our attention on provid-
ing solutions for sufferers of body dismorphic disorder and a variety
of phobias.
We begin by developing flexible simulations in order that patients
receive the most effective sensory stimulus. Screening phases in the
treatment process shall allow identification of VEs and avatars best
suited to the pathology, and most conducive to offering the patient
an optimally comfortable experience. Avatar design is crucial as this
entity shall offer guidance and support while the patient navigates
their psychedelic experience. Avatars have already shown their
utility in schizophenia treatments [29, 56].
In prescribing composite therapies we shall decide drug, dosage,
and simulation combinations in a similar way to drug-only combina-
tions using the Chou-Talalay method [18]. We may categorize simu-
lation settings according to pathology while rating the expected po-
tency using the German VR Simulation Realism Scale [77]. Testing
shall initially take place using healthy subjects in order to establish
tolerance and gauge the effects of various psychedelic compound
on the sense of presence. Phase 2 sees patients who previously
responded well to drug-only interventions receive the combined
treatment. Here we gain insight into the increased efficacy of com-
bining treatment paradigms. Phase 3 shall attempt to treat those
hard cases who previously exhibited little or no improvement from
drug-only therapies.
Follow up visits and feedback shall inform how to proceed re-
garding the future development of composite treatments. The ef-
fectiveness of each novel composite treatment shall be assessed by
evaluating patients in follow up discussions and will rely upon self
reporting and clinical assessment by a psychiatrist. Acceptance of
novel treatments of this nature is naturally slow. Psychedelics will
take time to become an established part of medicine due to an ar-
guably checkered history and the resulting popular misconceptions
surrounding such compounds.
Whether or not the adoption of psychedelic medicine proves
to be straightforward, now is not the time to resist progressing the
knowledge of such novel interventions. The prevalence of depression
and anxiety [96], PTSD [71], and addiction [54] are all increasing.
Effective composite treatments such as those described can raise
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... Furthermore, implementing an appropriate control condition is a difficult task for VR methods which could be addressed in future research (i.e., developing suitable "placebo" VR experiences). Third, combining virtual or augmented reality with, for example, sensory deprivation methods or microdosing of psychedelics might also offer intriguing avenues of research (101,145,146). Fourth, the results of MEQ30 and EDI highlight some issues in using these questionnaires for VR experiences (see "Limitations"). ...
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Background Recent research has shown promising results for the therapeutic benefits of psychedelics. One popular view claims that these benefits are mediated by the subjective experiences induced by these substances. Based on this, we designed a virtual reality experience, Psyrreal, that mimics the phenomenological components of psychedelic experiences. Aims We aimed to investigate the therapeutic efficacy of Psyrreal and psychedelic VR experiences in treating depressive symptoms as well as explore the effect of Psyrreal on subjective factors which have been suggested to mediate the therapeutic benefits of psychedelics. Methods In this open-label feasibility study, thirteen participants with mild-to-moderate depression underwent a 2-day therapeutic intervention implementing Psyrreal. Depressive symptoms were evaluated by the Emotional State Questionnaire (EST-Q2) at the start of the intervention and 2 weeks after. A thematic analysis of semi-structured interviews after Psyrreal was also conducted as an additional assessment of the method. Results A 2-day intervention implementing Psyrreal led to significant decreases in depressive symptoms at the 2-week follow-up ( n = 10, p = 0.007, Hedges’ g = 1.046) measured by the Emotional State Questionnaire (EST-Q2). The analysis of semi-structured interviews suggests that Psyrreal could lead to insight and alterations in the sense of self in some people. Conclusion This work proposes a novel method using virtual reality to augment the treatment of psychological disorders as well as to precisely investigate the mediating subjective factors of the therapeutic effects of psychedelic substances. Our preliminary results suggest that VR experiences combined with psychological support show potential in treating depressive symptoms and further research into similar methods is warranted.
... Whilst these two different therapeutic approaches have developed separately, but in parallel, consideration has recently been given to a composite approach in order to enhance efficacy (Moroz and Carhart-Harris, 2018). For example, it has been suggested that VR might be used to optimize the environment in psychedelic sessions (Aday et al., 2020). ...
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Psychotherapy with the use of psychedelic substances, including psilocybin, lysergic acid diethylamide (LSD), ketamine, and 3,4-methylenedioxymethamphetamine (MDMA), has demonstrated promise in treatment of post-traumatic stress disorder (PTSD), anxiety, addiction, and treatment-resistant depression. Psychedelic-assisted psychotherapy (PP) represents a unique psychopharmacological model that leverages the profound effects of the psychedelic experience. That experience is characterized by strong dependency on two key factors: participant mindset and the therapeutic environment. As such, therapeutic models that utilize psychedelics reflect the need for careful design that promotes an open, flexible, trusting mindset and a supportive setting. To meet this need, the PP model is increasingly supplemented by auxiliary methods, including meditation, relaxation, visualization or spiritual practices. We suggest virtual reality (VR) as a full-spectrum tool able to capitalize on and catalyze the innately therapeutic aspects of the psychedelic experience, such as detachment from familiar reality, alteration of self-experience, augmentation of sensory perception and induction of mystical-type experiences. This is facilitated by VR’s evidenced capacity to: aid relaxation and reduce anxiety; buffer from external stimuli; promote a mindful presence; train the mind to achieve altered states of consciousness (ASC); evoke mystical states; enhance therapeutic alliance and encourage self-efficacy. While these unique VR features appear promising, VR’s potential role in PP remains speculative due to lack of empirical evidence on the combined use of VR and PP. Given the increased commercial interest in this synergy there is an urgent need to evaluate this approach. We suggest specific VR models and their role within PP protocols to inspire future direction in scientific research, and provide a list of potential disadvantages, side effects and limitations that need to be carefully considered. These include sensory overstimulation, cyber-sickness, triggering memories of past traumatic events as well as distracting from the inner experience or strongly influencing its contents. A balanced, evidence-based approach may provide continuity across all phases of treatment, support transition into and out of an ASC, deepen acute ASC experiences including mystical states and enrich the psychotherapeutic process of integration. We conclude that the potential application of VR in modulating psychedelic-assisted psychotherapy demands further exploration and an evidence-based approach to both design and implementation.
... The approach outlined herein, where aesthetic hyperparameters defining a particular journey can be precisely defined, offers an interesting complement to ongoing YD research, opening up a range of further research directions. [58] It will be interesting to explore how Isness variants, constructed by exploring different domains of the aesthetic hyperparameter space, compare to different YDEs. Enabling new phenomenological experiences by designing new YD molecules is difficult, and clinical research efforts therefore focus primarily on tuning set and setting. ...
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Studies combining psychotherapy with psychedelic drugs (PsiDs) have demonstrated positive outcomes that are often associated with PsiDs' ability to induce 'mystical-type' experiences (MTEs) - i.e., subjective experiences whose characteristics include a sense of connectedness, transcendence, and ineffability. We suggest that both PsiDs and virtual reality can be situated on a broader spectrum of psychedelic technologies. To test this hypothesis, we used concepts, methods, and analysis strategies from PsiD research to design and evaluate 'Isness', a multi-person VR journey where participants experience the collective emergence, fluctuation, and dissipation of their bodies as energetic essences. A study (N=57) analyzing participant responses to a commonly used PsiD experience questionnaire (MEQ30) indicates that Isness participants had MTEs comparable to those reported in double-blind clinical studies after high doses of psilocybin & LSD. Within a supportive setting and conceptual framework, VR phenomenology can create the conditions for MTEs from which participants derive insight and meaning.
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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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Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. TRIAL REGISTRATION: ISRCTN, number ISRCTN14426797. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
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Rationale: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
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Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
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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.
Background Major depression is associated with significant disability, morbidity, and mortality. The current study estimated trends in the prevalence of major depression in the US population from 2005 to 2015 overall and by demographic subgroups. Methods Data were drawn from the National Survey on Drug Use and Health (NSDUH), an annual cross-sectional study of US persons ages 12 and over (total analytic sample N = 607 520). Past-year depression prevalence was examined annually among respondents from 2005 to 2015. Time trends in depression prevalence stratified by survey year were tested using logistic regression. Data were re-analyzed stratified by age, gender, race/ethnicity, income, and education. Results Depression prevalence increased significantly in the USA from 2005 to 2015, before and after controlling for demographics. Increases in depression were significant for the youngest and oldest age groups, men, and women, Non-Hispanic White persons, the lowest income group, and the highest education and income groups. A significant year × demographic interaction was found for age. The rate of increase in depression was significantly more rapid among youth relative to all older age groups. Conclusions The prevalence of depression increased significantly in the USA from 2005 to 2015. The rate of increase in depression among youth was significantly more rapid relative to older groups. Further research into understanding the macro level, micro level, and individual factors that are contributing to the increase in depression, including factors specific to demographic subgroups, would help to direct public health prevention and intervention efforts.
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.
Virtual reality (VR) can provide our minds with direct access to digital media in a way that seemingly has no limits. However, creating compelling VR experiences is an incredibly complex challenge. When VR is done well, the results are brilliant and pleasurable experiences that go beyond what we can do in the real world. When VR is done badly, not only is the system frustrating to use, but it can result in sickness. There are many causes of bad VR; some failures come from the limitations of technology, but many come from a lack of understanding perception, interaction, design principles, and real users. This book discusses these issues by emphasizing the human element of VR. The fact is, if we do not get the human element correct, then no amount of technology will make VR anything more than an interesting tool confined to research laboratories. Even when VR principles are fully understood, the first implementation is rarely novel and almost never ideal due to the complex nature of VR and the countless possibilities that can be created. The VR principles discussed in this book will enable readers to intelligently experiment with the rules and iteratively design towards innovative experiences.