Predicting responses to psychedelics: a prospective study
This longitudinal survey study (n=654 > 535 > 379 > 315 > 212, with increasing dropout) gathered data from individuals at five different time points before and after they undertook a preregistered psychedelic experience, and assessed variables related to personality traits, intentions, and the set and setting to predict the acute effects of taking the psychedelic, as well as long-term outcomes of subjective well-being. Baseline trait variables, such as absorption, strongly influenced long-term well-being. However, acute variables such as the intention and intensity of having mystical experiences also positively influenced well-being up to four weeks after the psychedelic experience.
Authors
- Robin Carhart-Harris
- David Nutt
- Christopher Timmermann
Published
Abstract
Introduction
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.
Methods
Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). 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.
Results
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, as well 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 those 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.
Discussion
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.
Research Summary of 'Predicting responses to psychedelics: a prospective study'
βBlossom's Take
Introduction
Haijen and colleagues situate this study within the recent resurgence of clinical and experimental work on serotonergic psychedelics, noting that single-dose administrations (notably of psilocybin) have been reported to produce enduring improvements in psychological well-being and promising clinical effects across diverse disorders. They point out that, despite accumulating evidence of therapeutic potential, the ability to predict individual acute and longer-term responses to psychedelics remains limited. Prior work has linked acute ‘‘mystical’’ or ‘‘peak’’ experiences and trait absorption to favourable outcomes and identified some predictors of challenging experiences, but most existing studies are limited either to controlled settings (often with psilocybin only) or to prediction of acute effects rather than longer-term change. This paper therefore set out to collect prospective, naturalistic data to improve prediction of both the acute psychedelic experience and subsequent changes in psychological well-being. Using an online, longitudinal survey administered at five time points (1 week before, 1 day before, 1 day after, 2 weeks after and 4 weeks after a planned psychedelic experience), the investigators aimed to test two primary hypotheses: that subjective well-being (measured by the WEMWBS) would increase at 2 weeks post‑experience, and that features of the acute experience—particularly mystical-type experiences—would predict later changes in well-being. They also planned to examine the relative contributions of baseline trait variables, ‘‘set’’ and ‘‘setting’’ factors, intentions for the experience, and drug dose to acute and longer-term outcomes.
Methods
Haijen and colleagues used a prospective, opportunity-sampling design with web-based data collection. Inclusion criteria were age 18 or over, adequate English comprehension, and an intention to take a classic psychedelic in the near future (psilocybin/magic mushrooms/truffles, LSD/1P-LSD, ayahuasca, DMT/5‑MeO‑DMT, salvia divinorum, mescaline, or iboga/ibogaine). Participants registered on a bespoke website, provided informed consent, supplied a planned date for their experience, and received emails with unique identification links to complete five surveys timed to that date. The survey battery combined established instruments and a set of self-constructed items. Primary outcome was psychological well-being assessed by the 14-item Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Baseline trait measures included the Ten‑Item Personality Inventory (TIPI) for the Big Five domains, a shortened modified Tellegen Absorption Scale (MODTAS; 25 items), the short Spielberger State‑Trait Anxiety Inventory (STAI‑SF), the Short Suggestibility Scale (SSS) and a Stubborn Opinionatedness scale (SOP). Acute measures administered one day after the experience comprised the Altered States of Consciousness scale (OAV/11D‑ASC), from which a composite ‘‘visual effects’’ score was derived (elementary imagery, complex imagery, audio‑visual synaesthesia), the 30‑item Mystical Experience Questionnaire (MEQ), and the 30‑item Challenging Experience Questionnaire (CEQ). Doses were reported post‑hoc and converted into LSD-equivalent categories (low to extremely high). Several self-constructed items captured ‘‘set’’ (pre-state), aspects of the setting, and ten possible intentions for the experience (e.g. recreational, spiritual, therapeutic, to confront difficult emotions). Principal component analysis (PCA) with Varimax rotation reduced set/setting items into three components named ‘‘set,’’ ‘‘setting,’’ and ‘‘clear intentions,’’ and the intentions into three components labelled ‘‘spiritual connection,’’ ‘‘recreation,’’ and ‘‘emotional.’’ Sample sizes at each time-point were N = 654, N = 535, N = 379, N = 315 and N = 212 respectively. Statistical approaches included repeated-measures GLM ANOVA for WEMWBS change, independent t‑tests for subgroup comparisons, linear mixed models (to handle missing data) with time as a repeated effect to model well‑being over time and interactions with predictors, and multivariate GLM regression to predict acute MEQ, CEQ and visual-effects scores from traits, set/setting and dose. All predictor variables were standardised and an alpha of 0.05 was used.
Results
Participant recruitment yielded progressively smaller samples across the five surveys: 654 at baseline down to 212 at the 4‑week follow‑up, with some participants reporting additional psychedelic experiences during follow‑up (88 at 2 weeks, a further 29 at 4 weeks). PCA of the 12 self-constructed set/setting items produced three components explaining 54.33% of variance: ‘‘set’’ (31.12%), ‘‘setting’’ (12.49%) and ‘‘clear intentions’’ (10.72%). PCA of the ten intention items also produced three components explaining 55.14% of variance: ‘‘spiritual connection’’ (26.88%), ‘‘recreation’’ (16.24%) and ‘‘emotional’’ (12.01%). Psychological well‑being (WEMWBS) increased at 2 weeks after the psychedelic experience and remained elevated at 4 weeks compared with baseline. In subsequent mixed-model analyses, a range of relationships were identified. Baseline trait absorption and higher reported drug dose were positively associated with all acute measures: MEQ (dose F(181)=16.07, p<0.001; absorption F(181)=21.11, p<0.001), CEQ (dose F(181)=8.03, p<0.006; absorption F(181)=6.82, p<0.020) and visual effects (dose F(181)=21.05, p<0.001; absorption F(181)=8.98, p<0.004). The multivariate models explained R² = 0.342 for MEQ, R² = 0.324 for CEQ and R² = 0.211 for visual effects. Predictors of mystical‑type (MEQ) scores included clear intentions (F(181)=6.30, p<0.020) and a trend for the spiritual‑connection intention (F(181)=3.75, p≈0.06). Challenging experiences (CEQ) were negatively predicted by the ‘‘set’’ component (F(181)=21.09, p<0.001) and by the ‘‘recreation’’ intention component (F(181)=7.72, p<0.007); the ‘‘setting’’ component showed a trend towards reducing CEQ scores (F(181)=3.33, p≈0.08). Clear intentions also positively predicted visual effects (F(181)=4.61, p<0.040). When modelling change in well‑being over time with a broad set of predictors, baseline trait variables emerged as particularly influential. Trait anxiety showed the strongest effect on well‑being change, evidenced by a significant time-by-trait‑anxiety interaction (F(172)=3.93, p<0.030); trait anxiety was negatively associated with baseline WEMWBS and with WEMWBS at 4 weeks but not at 2 weeks, suggesting transient attenuation of its negative association at 2 weeks. Number of lifetime psychedelic uses interacted with time (F(106)=6.11, p<0.004): more lifetime uses were negatively associated with WEMWBS at 2 and 4 weeks (t(136)=-3.29, p<0.002; t(96)=-2.61, p<0.020), indicating smaller well‑being gains in more experienced users. Individuals self‑rating as ‘‘highly experienced psychedelic users’’ had higher WEMWBS scores overall at baseline and follow‑ups. Baseline openness predicted baseline and 2‑week WEMWBS; emotional stability, clear intentions and visual effects correlated with baseline WEMWBS but did not predict change. The ‘‘setting’’ component was positively associated with WEMWBS at 2 weeks (t(139)=2.11, p<0.040) with a trend at 4 weeks. Finally, being in a self‑reported therapeutic environment did not show consistent effects on acute experience measures in these analyses.
Discussion
Haijen and colleagues interpret their findings as supporting the importance of both extra‑pharmacological factors (set, setting and intentions) and stable baseline traits in shaping psychedelic responses. They highlight three central conclusions: first, psychological well‑being increased at 2 weeks and remained elevated at 4 weeks after a naturalistic psychedelic experience; second, mystical‑ or peak‑type acute experiences were positively associated with later increases in well‑being, whereas challenging experiences were associated with lower well‑being across time; third, in a more comprehensive model that included traits, set/setting, intentions, dose and acute measures, baseline trait variables—particularly trait anxiety and number of lifetime uses—explained the largest proportion of variance in well‑being change. The authors position these results alongside prior literature showing a link between mystical/peak experiences and positive longer‑term outcomes and prior reports implicating absorption and dose in intensifying psychedelic effects. They note that mystical‑type and challenging experiences are not mutually exclusive and that existing instruments may not capture whether challenging periods were ultimately resolved into therapeutic breakthroughs; they therefore advocate development of measures sensitive to ‘‘breakthrough’’ or cathartic outcomes. Haijen and colleagues also discuss the therapeutic relevance of preparing participants to have clear intentions and a positive pre‑state, and of ensuring a comfortable setting, because these factors predicted more favourable acute profiles (more mystical‑type, fewer challenging experiences). The authors acknowledge multiple limitations inherent to the web‑based observational design: reliance on self‑reported timing and dose (dose estimates were collected after the experience and may be biased by subjective intensity), uncertain compliance with scheduled surveys, sample attrition across time-points, and likely selection bias towards individuals motivated and positively disposed to psychedelic use. They also note the limited operationalisation of ‘‘therapeutic setting’’ in their items and the broader debates about the construct validity of ‘‘well‑being’’ as an outcome. For future work, they recommend refining measurements of setting, developing an ‘‘emotional breakthrough’’ questionnaire, recruiting more heterogeneous samples (to examine cultural, religious or superstitious moderators), and pursuing controlled studies to further test and refine predictive models. Ultimately, the investigators propose that iterative, empirically derived guidelines could help inform clinical decisions about whether, when, where and how to dose with psychedelics, with the aim of reducing risks and maximising benefit.
Conclusion
The authors conclude that, in this large prospective naturalistic sample, baseline trait variables were the most potent predictors of change in psychological well‑being after a psychedelic experience. Mystical‑type (peak) acute experiences were positively related to well‑being change, while challenging experiences showed a general negative association. Clear intentions and feeling prepared (positive ‘‘set’’), together with intentions related to spiritual connection or recreation, were conducive to peak experiences and protective against challenging experiences. Higher trait absorption and larger reported doses intensified acute experiences and increased the likelihood of both mystical and challenging elements. The authors emphasise that much variance remains unexplained and call for further controlled and prospective research to refine prediction models and to develop empirically grounded guidelines for clinical use.
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RESULTS
A principle component analysis was done to the set and setting items that were self-constructed (see Table) and for the 10 different intentions to have a psychedelic experience (see Table). This was done to reduce dimensionality and to find a general structure underlying these overlapping items, which could then be used in the subsequent analyses. Both principle component analyses were performed using IBM SPSS Statistics version 24, using the principle component method and an orthogonal rotation (Varimax). The appropriate number of factors was determined after investigating Cattell's scree plot and by the cut-off of eigenvalues larger than one. A GLM repeated measures ANOVA was performed to evaluate the changes in well-being scores. WEMWBS scores were included as dependent variable with time as within-subject effect. The following variables were included as covariates to control for confounding effects on well-being scores: age, sex, employment status, educational level, number of lifetime uses of a psychedelic, multiple psychedelic experiences during their enrolment in the study, and four items asking about the individual's relationship with psychedelic drugs: "I am an active advocate of psychedelic drug use," I am an active advocate of the therapeutic use of psychedelics," I have an advanced knowledge about psychedelics," and "I am a highly experienced psychedelic drug user." Only the covariates that showed a significant effect will be included in the further analyses. To further investigate the changes in well-being, independent t-tests have been performed to compare mean values for the following variables between those who decreased in wellbeing compared to those who did not show any change, or increased in well-being: baseline WEMWBS score, the personality traits openness to experience (TIPI), emotional stability (TIPI), absorption (MODTAS), suggestibility (SSS), stubbornness (SOP), trait anxiety (STAI), the three components underlying intentions: "spiritual connection, " "recreation" and "emotional, " the three components underlying set and setting: "set, " "setting," and "clear intentions, " drug dose, the variable being in a therapeutic environment, the total scores of the MEQ and CEQ and the visual effects score, based on the elementary imagery, complex imagery and audio-visual synaesthesia subscales of the OAV. To examine relationships between variables of interest, linear mixed models were used in the MIXED procedure of IBM SPSS Statistics version 24. A mixed model analysis was chosen because of its ability to handle missing data and use all existing data. The model following from our hypothesis included the WEMWBS as the dependent variable and time as a repeated effect, with an unstructured covariance structure. This model contained in the fixed part: time, number of lifetime uses of a psychedelic, the item "I am a highly experienced psychedelic drug user", MEQ, CEQ, visual effects, and all two-way interaction terms between time and the variables: number of lifetime uses of a psychedelic, the item "I am a highly experienced psychedelic drug user", MEQ, CEQ, and visual effects. The next model was included to assess what type of variable (i.e., traits, set and setting, intentions, drug dose, or acute psychedelic measures) was most influential in predicting well-being changes. The model included the WEMWBS as the dependent variable and time as a repeated effect, with an unstructured covariance structure. This model contained in the fixed part: time, number of lifetime uses of a psychedelic, the item "I am a highly experienced psychedelic drug user," the personality traits openness to experience (TIPI), emotional stability (TIPI), absorption (MODTAS), suggestibility (SSS), stubbornness (SOP), trait anxiety (STAI), the three components underlying intentions: "spiritual connection, " "recreation," and "emotional, " the three components underlying set and setting: "set, " "setting," and "clear intentions, " drug dose, the variable being in a therapeutic environment, the total scores of the MEQ and CEQ, visual effects, and all two-way interaction terms between time and the variables described above. Next, a GLM multivariate linear regression model was used to evaluate what variables were able to predict measures related to the acute psychedelic experience. The total scores of the MEQ, CEQ and visual effects were used as dependent variables. Included as independent variables were: number of lifetime uses of a psychedelic, the item "I am a highly experienced psychedelic drug user," the personality traits openness to experience (TIPI), emotional stability (TIPI), absorption (MODTAS), suggestibility (SSS), stubbornness (SOP), trait anxiety (STAI), the three components underlying intentions: "spiritual connection, " "recreation," and "emotional, " the three components underlying set and setting: "set, " "setting," and "clear intentions, " drug dose, and the variable being in a therapeutic environment. Tests for multicollinearity between variables have been done before running the analyses. All variables were standardized before being entered into the analyses. Lastly, for all statistical tests, an alpha of 0.050 was used.
CONCLUSION
The present study used an entirely novel approach to address the important question of how best to predict both acute and longer-term responses to psychedelic compounds. Its primary aim was to test for changes in subjective well-being and then test predictive models of such changes. As hypothesized, wellbeing was found to be increased 2 weeks after a psychedelic experience and remained increased at 4 weeks. This finding is in line with those of several previous studies, some of which observed improvements in well-being after a single administration of a psychedelic that persisted for over one year. Comparing the well-being scores found in the current study to normative WEMWBS data showed that the current sample had baseline well-being scores that were slightly lower than the general population.However, 2 weeks after the psychedelic experience, the mean well-being score became slightly higher than that for the general population. At 4 weeks after the experience, the mean wellbeing score was still higher compared to the normative data, although this difference was not significant. Thus, the principle that psychedelics generally enhance psychological well-being, even in already healthy individuals, appears to be supported by the present study's data. In the current study, we compared individuals showing no change or an increase in well-being to those decreasing in wellbeing after a psychedelic experience. The only difference found included lower baseline well-being scores in the subsample that showed increases in well-being. This could mean that there was more scope for change after a psychedelic experience in these individuals compared to those who decreased and had a higher baseline level of well-being to begin with. To elaborate on this, we found a modest correlation between the number of lifetime uses of a psychedelic and baseline well-being scores [r (654) = 0.21, p < 0.001], meaning that those who used psychedelics more often in the past had a higher level of well-being at baseline (see the Supplementary Material for a correlation matrix of the variables of interest described in this study). This positive association between psychedelic use and psychological well-being is supported by a large-scale population study in which suicidality and psychological distress were both lower in psychedelic "users" vs. matched non-users. These findings reinforce the view that psychedelics are an anomaly among drugs of potential misuse, as, with appropriate caveats regarding context of use, use of psychedelics appears to be positively rather than negatively associated with mental health. Further, a negative correlation between the number of lifetime uses of a psychedelic and change in well-being scores [r (279) = -0.23, p < 0.001] was found, meaning that those who had more experience with psychedelics in the past showed less improvement in well-being after the psychedelic experience, which is in line with the finding that these individuals had higher well-being scores at baseline.
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Study Details
- Study Typeindividual
- Populationhumans
- Characteristicssurveyfollow up
- Journal
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