Predicting Responses to Psychedelics : A Prospective Study, Eline C. H. M. Haijen et al., 2018

Predicting Responses to Psychedelics : A Prospective Study

Eline C. H. M. Haijen, Mendel Kaelen, Leor Roseman, Christopher Timmermann, Hannes Kettner, Suzanne Russ, David Nutt, Richard E. Daws, Adam D. G. Hampshire, Romy Lorenz  and Robin L. Carhart-Harris

Frontiers in Pharmacology, 2018

doi: 10.3389/fphar.2018.00897



Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey ( Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points were N = 654, N = 535, N = 379, N = 315, and N = 212 respectively. Psychological well-being was increased 2 weeks after a psychedelic experience and remained at this level after 4 weeks. Higher ratings of a “mystical-type experience” had a positive effect
on the change in well-being after a psychedelic experience, whereas the other acute psychedelic experience measures, i.e., “challenging experience” and “visual effects”, did not influence the change in well-being after the psychedelic experience. Having “clear intentions” for the experience was conducive to mystical-type experiences. Having a positive “set” as well as having the experience with intentions related to “recreation” were both found to decrease the likelihood of having a challenging experience. The baseline trait “absorption” and higher drug doses promoted all aspects of the acute experience,
i.e.,mystical-type and challenging experiences, aswell as visual effects. When comparing the relative contribution of different types of variables in explaining the variance in the change in well-being, it seemed that baseline trait variables had the strongest effect on the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping
to mitigate risks while maximizing potential benefits in an evidence-based manner.

Keywords : psychedelics, predicting response, well-being, acute effects, peak experience, mystical experience, challenging experience, set and setting



There has been notable increase in the volume of clinical research on serotonergic psychedelics within the last decade (Carhart- Harris and Goodwin, 2017). Naturally occurring psychedelics such as psilocybin-containing mushrooms have been used as medicines for centuries, and in the mid twentieth century, some of these and the newly synthesized psychedelic LSD, were briefly explored by the Western medicine. The present revival of interest in psychedelics has been described as a “renaissance” (Sessa, 2012). One particularly notable finding within the present era is that a single dose of psilocybin led to an increase of psychological well-being that endured for at least one year (Griffiths et al., 2008, 2011; Garcia-Romeu et al., 2014). Recent results have suggested that diverse clinical populations can benefit from psychedelics, with rapid and enduring improvements in mental health outcomes seen after treatment with psychedelics for a range of different disorders (Griffiths and Grob, 2010; Anderson
et al., 2012; Bogenschutz and Pommy, 2012; Bogenschutz and Johnson, 2016; Mithoefer et al., 2016; Johnson and Griffiths, 2017; Nichols et al., 2017), for a review see Carhart-Harris and Goodwin (2017). Despite these developments, little progress has been made in our ability to predict, ahead of time, the nature of individual responses to a psychedelic (although see Carrillo et al., 2018).

The importance of assessing the potential of psychedelics to treat major psychiatric disorders such as depression and addiction, that are highly prevalent, costly, and for which current treatments have significant limitations (Chisholm et al., 2016), is becoming increasingly well recognized (Carhart-Harris and Goodwin, 2017; Carhart-Harris et al., 2017). However, given the improvements in well-being seen in healthy volunteers after experiences with psychedelics (Griffiths et al., 2006, 2008), it also seems relevant to consider their effects in the general population, not least because prevalence of use in the West remains high (Krebs and Johansen, 2013a,b;Winstock, 2017) and will increase considerably if current efforts to medicalise psychedelics are successful.

A limited number of previous studies have attempted to assess factors that may be predictive of acute or longer-term responses to psychedelics. Perhaps the earliest was carried out by Leary et al. (1963) who found that the level of reported apprehension before taking psilocybin was negatively correlated with the pleasantness of the subsequent experience and willingness to repeat it (Leary et al., 1963). A related finding of anticipatory anxiety predicting acute anxiety during a psychedelic experience was reported by
the same team (Metzner et al., 1965). Richards et al. (1977) found that those who had a “peak experience” (Maslow, 1959, 1964, 1968), described as experiencing disorientation in space and time, feelings of being free of inner conflict, feelings of awe, amazement and humility, and a sense of oneness with the universe, were less hostile, tense and anxious beforehand. The authors explained this by the observation that these individuals were more engaged in the therapeutic process, more willing to confront anxiety and less frightened by the prospect of self-confrontation (Richards et al., 1977). Similarly, Metzner et al. (1965) found that those with positive prior expectations for their experience did indeed have more positive experiences under a psychedelic (Metzner et al., 1965).

The most notable modern study to have assessed prediction of response was carried out by Studerus et al. (2012). Here, data pooled from23 controlled studies involving over 250 participants was used to identify factors predictive of response to psilocybin. The findings included that baseline trait “absorption” and being psychologically “well” in the days prior to the experience, were predictive of peak experiences, whereas younger age, emotional excitability prior to the experience, and being in a positron
emission tomography scanner, were all predictive of unpleasant, “challenging experiences” (i.e., experiences characterized by anxiety, psychological struggle, fear, panic and/or paranoia).

While this study is useful, it is limited to predicting just the acute experience with psilocybin and does not address longerterm effects or responses to other psychedelics. Neither is it reflective of the importance of non-pharmacological variables present when psychedelics are used therapeutically. Regarding longer-term outcomes, a growing number of controlled studies with psychedelics are endorsing the view that the occurrence of a “mystical-type” experience is predictive of positive longterm outcomes (O’Reilly and Funk, 1964; Klavetter and Mogar, 1967; Pahnke et al., 1970; Kurland et al., 1972; Richards et al., 1977; Griffiths et al., 2011, 2016; MacLean et al., 2011; Garcia- Romeu et al., 2014; Bogenschutz et al., 2015; Ross et al., 2016; Roseman et al., 2017). The term “mystical-type experience” is based on Walter Stace’s work on mysticism (Stace, 1960), and is effectively synonymous with the term peak experience, derived from the work of psychologist Abraham Maslow (Maslow, 1959, 1964) described earlier. There is mixed data on the relationship between challenging psychological experiences and longer-term outcomes, with one study suggesting that challenging experiences can be beneficial, but not if the duration of struggle dominates the entire experience (Carbonaro et al., 2016). It has also been
shown that the personality trait neuroticism is predictive of the occurrence of a challenging experience (Barrett et al., 2017).

The present study was conceived as a way of reducing uncertainty about how an individual might respond to a psychedelic. Our hope is that such an endeavor may ultimately serve to guide critical decisions about whether, when and how to dose for a psychedelic experience. We wished to combine predictions of acute experience with those of longerterm changes, to track, within the same time-limited study, the processes of potential change occurring within individuals after a psychedelic experience. To do this, we set up a web-based survey embedded within a purpose-built website1 that could record subjective data at five crucial time points: (1) 1 week before, (2) within 1 day before, (3) within a few days after, (4) 2 weeks after, and (5) 4 weeks after a psychedelic experience.

Individuals were invited to sign up for the survey if they planned to have a psychedelic experience within the near future. After electronically declaring informed consent, participants stated the expected date for their experience and provided their email addresses via which reminders were sent for them to complete the relevant surveys at the relevant time points. Measures were used to assess psychological well-being (which served as the primary outcome) as well as the acute psychedelic experience. Data reduction methods were used to generate principal components underlying “set” and “setting” factors as
well as a variety of intentions for the psychedelic experience, which served as independent variables. A range of potential trait predictor variables weremeasured at baseline and are listed in the
methods section.

Our primary hypothesis was that subjective well-being would be significantly increased 2 weeks after the psychedelic experience compared to baseline. Secondly, it was hypothesized that the nature of the acute psychedelic experience would be predictive of subsequent changes in well-being (Roseman et al., 2017). Specifically, it was hypothesized that mystical-type experiences (Stace, 1960) under the psychedelic would be positively related to subsequent improvements in well-being. The contribution of “set” factors relating to the pre-state (i.e., one’s state of mind immediately prior to taking the psychedelic), setting, as well as different trait variables and intentions for having the psychedelic experience to the subsequent nature of the acute psychedelic experience were assessed.