Psychedelics and the essential importance of context

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being associated with longer-term psychological benefits, has been highlighted and discussed elsewhere. 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. Crucially, in cases where 'set' and 'setting' were intentionally neglected or even manipulated in a negative way, outcomes were considerably less positive, such as in military experiments with psychedelics in the 1950s and 60s. It is right to acknowledge that cases of worsened mental health after controlled administrations of psychedelics have been reported; but seefor meta-analyses of prevalence data in controlled research, andfor relevant population-level data) and associated legal cases have been fought and won by plaintiffs (but see. 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. 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. Moreover, if the media and associated public opinion were to turn against psychedelics, as occurred in the mid to late 1960s, it is logical to suppose that this, in turn, would impact on expectations, and subsequently experience, in a selfreinforcing positive feedback loop(Figure). We should be conscious to avoid such a shift in 'cultural set and setting' with regards to psychedelics, particularly if is initiated by misinformation under a political agenda, as occurred in the late 1960s. 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 proponents (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 psychedelics 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 psychological distress, mood disorders and addiction. 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 experiences) and manipulation of the therapeutic environment, for example, with low lighting, carefully selected music playlists, aesthetically pleasing décor and implicit as well as explicit priming. Moreover, patients enrolled within modern psychedelic trials typically have access to two compassionate mental health professionals. These 'sitters' or 'guides' serve to carefully prepare the patient for their upcoming experience, support them during it, and help them integrate its content and meaning afterwards. Such intensive support is unusual in the context of conventional mental healthcare services, and despite its questionable feasibility in terms of time and associated costs, it has been the norm in modern psychedelic trials. In a similar way to how Good Clinical Practice training ensures a standard of practice in clinical research, specific training for psychedelic therapy may need to be developed, standardised and licensed if patient safety is to be maintained. With large clinical trials of psilocybin for treatment-resistant depression planned in the near future, it is reassuring that such matters are currently being addressed. We share the view of othersthat the experiential component of psychedelics necessitates and facilitates the development of a strong therapeutic bond between the patient and his/her guides. Moreover, although this way of working might initially 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. 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 psychedelicand so perpetuating the process. healthcare practice. Therapeutic alliance is already known to be a major predictor of response in mental healthcareand if the present thesis is correct, its influence is likely to be greater still in the context of psychedelics (see. 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. It seems unlikely that such effects can be attributed entirely to conventional 'positive expectancy' -the basis of the standard placebo effect-although seeand-nor to a low-level pharmacological effect if presumed-inactive doses of the experimental drug are used as the control (e.g. 1 mg/70 kg for 75% of the patients in. Most likely in our view, is a favourable-context effect mediated by positive expectancy and exceptional 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. Comprehensive approaches to drug action, that properly acknowledge context, have been gaining traction in psychopharmacology in recent years, as evidenced by seminal gene × environment, drug × cognition, and drug × environmentinteraction work. The central argument of the present paper is that at least the same degree of emphasis needs to be placed on extra-pharmacological factors in relation to psychedelics -Figure(see. Indeed, in line with recent hypothesesand findings, it is proposed that the pro-plasticity effects of serotonin-and serotonin 2A receptor agonism particularly) -renders the psychedelic experience exceptionally sensitive to context. Insufficient appreciation 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. Remarkably, despite its widespread adoption among psychedelic researchers, few controlled studies have ever been performed to test the assumed relationship between psychedelics and context (although see. In terms of our own research, the closest we have come to testing this has been to investigate the influence of music, positive autobiographical memory scriptsand creative imagery/suggestibility on the psychedelic experience, 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 psilocybin therapy sessions is predictive of the quality of their experience, which in turn is predictive of long-term therapeutic outcomes. It is logical to infer from such findings that psychedelics' specific pharmacology works synergistically with context, creating a certain kind of experience that is conducive to particular outcomes (Carhart-Harris and. Increased serotonin 2A receptor signalling mediating cortical plasticity and an associated sensitivity 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. 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 emotional and cognitive state. Relatedly, we have often observed that participants are relatively insensitive to conventional task-based stimuli under psychedelics, as the relevant stimuli fail to engage their attention and/or interest (seefor a relevant discussion). Looking to the future, it seems vital that new studies be conducted to test the hypothesised primacy of context in shaping 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, and on this basis, the quest for a non-psychedelic but still therapeutically effective 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 therapeutic efficacy equivalent to that of ketamine. 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 psychological response. There is also evidence that spatially confined neuroimaging settings can increase the likelihood of challenging experiences with psychedelics. This is something we have witnessed on at least two occasions (in approximately 100 psychedelic scan sessions) with magnetic resonance imaging and magnetoencephalography separately -although in retrospect, both cases of transient anxiety may have been as much to do with negative 'set' as the 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 integration, as is default in most (if not all) recent and current clinical trials. Other than the aforementioned dose-response study) and retrospective analyses (e.g., controlled studies designed to isolate and test key contextual variables assumed to influence the quality of a psychedelic experience have not yet been carried out (but see. 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. One way to resolve this matter may be to design a study involving low doses of a psychedelic, in which the provision of a suboptimal 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. While there is as yet no published peerreviewed 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. 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. A controlled study designed to test this would add value, not just in terms of providing a timely examination of the current claims about microdosing, but also by testing the potentially important association between serotonin 2A receptor signalling and sensitivity to context. Back-translation involving comparable environmentaland more selective pharmacological manipulationsin nonhuman 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 testing those elements about which we hold particularly strong prior hypotheses (e.g., that music and psychotherapy are critical components of the treatment model) but there may also be another, supplementary approach. Psychedelics are an anomaly among drugs of 'potential misuse', 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. Exploiting this phenomenon, we recently set up a web-based survey system (psychedelicsurvey.com) in which individuals who plan to take a psychedelic can enter the date of their planned experience and then receive specific surveys at strategic time points: (a) 1 week before, (b) 1 day before, (c) 1 day after, and then (d) 2 weeks after the focal experience. In this way we sought to test the process of change related to a psychedelic experience, assessing a large number of potentially salient factors and their relevant contributions to acute and longer-term outcomes in a large sample. Preliminary results from this project can be seen in Figure(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-that can effectively be viewed as a synonymous with the concept of a 'mystical' experience. Conversely, model 2 reveals that the same factors -plus being in the company of well-trusted individuals -protect against a 'challenging' psychological experience (what some might refer to, perhaps too crudely, as a 'bad trip'). Consistent with previous work, we found that having a peak experience is predictive of improvements in psychological well-being 2 weeks after the experience (model 1), whereas having 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 experience 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. Briefly, based on additional measures included in this project, we are presently working towards resolving putative inconsistencies between our data and previous findings. More specifically, whereas we saw a trend relationship between challenging 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. Potentially resolving this discrepancy, we believe that challenging experiences can indeed be therapeutically beneficial but only if personal insight and/or an emotional catharsis follows the relevant experience(s) of psychological struggle. To test this assumption, we are presently developing an 'emotional breakthrough' measure, which was applied in the presently described survey project to good effect. It is also worth noting that previous studies supporting the therapeutic potential of challenging experiences required that participants focus on their most challenging psychedelic experience. Moreover, the 'long-term' outcomes shown in Figureare 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 psychedelic experience. 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 usewhich have (disproportionately) contributed to their historical negative stigma. The more optimistic and progressive counterpart to this, however, is that a careful and honest management of context may serve to minimise harm and maximise the considerable therapeutic potential of psychedelics, yielding a powerful treatment model with a compelling neuropsychological action that could potentially benefit a broad cross-section of the populace. 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 synergies may form part of an important paradigm shift in psychiatric care. Another view, however, is that factoring in context is problematic, since it (over)complicates traditional pharmacological models by adding extra psychological variability and practical 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 flawedand that the psychedelic treatment model, while costlier in terms of delivery, may actually be cost-saving in terms of therapeutic actiondue to the potential long-term duration of clinical response after just a small number of treatment sessions (Carhart-Harris and Goodwin, 2017). 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. ). 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. 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 (;. With regards cultural context (see Figure.), one might even consider a crosscultural 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). For the sake of science and healthcare over politics, we must hope that the future be allowed to properly test and tell.