This review (14 studies) found that traits of absorption, openness, acceptance, and surrender correlated with more positive and mystical (MEQ30) experiences. Gender didn’t predict drug effects, but possible biomarkers are serotonin receptor binding potential, executive network node diversity, and right anterior cingulate cortex volume.
Abstract
“Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field’s current understanding of how to predict acute reactions to psychedelic drugs.“
Authors: Jacob S. Aday, Alan K. Davis, Cayla M. Mitzkovitz, Emily K. Bloesch & Christopher C. Davoli
Notes
This paper was also covered in an interview for Ohio State News.
Summary
Psilocybin, LSD, ayahuasca/DMT, and mescaline are classic psychedelic drugs that can induce myriad cognitive, emotional, and neurological effects. However, little is known about participant states or traits that may predict acute psychedelic outcomes.
Although there is currently little consensus on how to predict how participants will react to psychedelics based on their individual characteristics, there is some agreement that the setting in which a psychedelic is given may be critical to predicting if individuals will experience therapeutic effects.
The effects of psychedelics are dose-dependent. The ideal dosage for optimizing treatment outcomes while minimizing adverse reactions is somewhere in the range of 5-30 mg/70 kg, but much is still unknown about individual state or trait factors that may interact with known predictors like dosage.
Researchers screen potential participants for psychedelic drug use based on their psychiatric and medical history. Individuals with uncontrolled hypertension, schizophrenia, psychotic disorders, and bipolar disorders are excluded, as are pregnant women and those with inadequate birth control practices.
Researchers have reviewed the contemporary research on baseline variables that have been shown to predict acute psychedelic drug effects. The results show that there is currently little consensus in the field on participant characteristics that can be used to predict acute psychedelic drug effects.
Two authors independently completed the systematic search in PubMed using six psychedelic-related terms and seven predictor-related terms, and applied an initial filter to select for language (English), species (human), and year (1994present).
After filtering for language, species, and year, 14 articles were examined for inclusion in the systematic review. The authors identified 10 articles that met the selection criteria, and 4 others were identified by the authors from outside sources.
The review included 10 articles using psilocybin, 2 using LSD, 1 using ayahuasca, and 1 examining psychedelic use in general. The median year of publication was 2018, suggesting that this is an emerging area of research.
Psilocybin. One study found that predrug individual differences in 5-HT2AR binding potential predicted how individuals responded to psilocybin.50 Lower baseline 5-HT2AR binding was associated with longer peak effects, a more rapid decrease in subjective drug intensity (SDI), and higher ratings of mystical-type experience.
In a placebo-controlled trial, individuals with a lower diversity of executive network nodes at baseline were more likely to experience ego dissolution under the influence of psilocybin.
A placebo-controlled study found that rACC thickness could predict aspects of the psychedelic experience. The authors hypothesized that activity in the cingulate cortex may underlie the profound emotional experiences induced by psychedelics.
Bienemann et al.43 found that female users reported bad trips more frequently, but the effect size was small.
Contradicting these results, Russ et al.46 found that ego dissolution and mystical-type experiences were positively related to baseline measures of surrender, absorption, and spiritual motivations, and negatively correlated with measures of deservingness and apprehension.
In another study, Russ and colleagues47 found that surrender and absorption were moderately to strongly related to the extent to which one had a mystical-type experience, and that dread was negatively related to baseline measures of preoccupation and confusion.
Psilocybin use in combination with mindfulness meditation was associated with positive attitudes toward life, openness, acceptance, and meditation depth. Mystical-type experiences were also positively related to optimistic attitudes toward life, openness, and meditation depth.
Studerus et al.40 identified several states and traits that were predictive of acute effects, including absorption, oceanic boundlessness, blissful states, and complex imagery. Age was negatively related to acute impairments in control and cognition, and emotional excitability predicted acute increases in spiritual experience, insightfulness, audiovisual synesthesia, and anxiety.
Stauffer and colleagues49 administered psilocybin to long-term AIDS survivors experiencing demoralization. They found that those high in the trait of attachment anxiety were more likely to have mystical-type experiences, and those high in attachment avoidance were more likely to have challenging experiences.
A retrospective study of psilocybin users found weak but statistically significant relationships between age and history of hallucinogen use with difficulty of the experience.
Two articles were included that identified baseline measures predicting the acute effects of LSD, but both studies relied on the same sample of participants and had small and nondiverse samples, variable dosages, and participants had considerable past experience with the drug.
Ayahuasca. One study found that experienced users had less impairment than occasional users on a test of executive functioning, and that this impairment was inversely correlated with lifetime ayahuasca use.
In a prospective study, users were surveyed 1 week prior, 1 day before, 1 day after, 2 weeks after, and 4 weeks following the day they planned to use a psychedelic. The trait of absorption was once again an important predictor of effects.
■ DISCUSSION
This review indicates that there may be baseline traits and states that are important to consider when predicting psychedelic drug effects.
Traits, such as 5-HT2AR binding potential, executive network node diversity, and rACC volume, were shown to be related to the acute cognitive and emotional effects of psychedelic drugs. However, only one study found that adverse reactions were more likely to be reported by female users.
Absorption was the personality trait most consistently linked to psychedelic drug reactions, and was also a predictor of mystical-type experiences. Moreover, absorption is related to 5-HT2AR binding potential, which may be a biomarker for predicting psychedelic drug effects.
A set of personality traits related to absorption, openness, and acceptance may prime individuals to fully immersive themselves in a nonordinary state.
One’s personal history of psychedelic use was shown to predict how individuals responded on several measures. This suggests that users may habituate to the effects of psychedelics over time, and it may be important to not overuse psychedelic substances in order to continue deriving the same benefits.
Individuals’ expectations and mood immediately prior to drug intake were found to be critical variables in determining acute psychedelic effects. Those in an open and positive mindset were more likely to derive benefits, whereas those in an unstable state or negative mindset were more likely to experience adverse effects.
In addition to expectations, mood, and traits, researchers should consider patients’ intentions when predicting how an individual will respond to a psychedelic drug.
As age increased, participants experienced less intense effects, both positive and negative. Older individuals may be less sensitive to the effects of psychedelics drugs and/or require higher doses.
This review identified a number of potential baseline predictors of drug effects, but many studies were compromised by open-label designs, small sample sizes, and homogeneous samples. Additionally, many studies have not yet been replicated, and some researchers fail to report when there is an absence of a relationship between variables.
Future researchers should compare the relative importance of baseline variables related to drug effects, and should particularly evaluate the trait of absorption and state of surrender, as they are consistently related to positive experiences with psychedelic drugs.
If state-level factors such as absorption are important for positive responses to psychedelics, then microdosing psychedelics before a full treatment dose may be beneficial.
■ CONCLUSION
Several baseline biological measures were found to be related to acute reactions to psychedelic drugs, including 5-HT2AR binding potential, executive network node diversity, and rACC volume. Increased age and experience with psychedelics were also related to less intense effects with the drugs.