Can We Predict Who Will Benefit From Psychedelic Therapy?

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Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects

By Steven Rowe

Media and popular culture have often portrayed psychedelic experiences as widely varied in nature, with extremes in both positive and negative directions. The reality in modern psychedelic therapy and research is far from this. In academic and clinical settings, rigorous screening is conducted to minimize the risk associated with use of psychedelic drugs. Things like medical and psychiatric history are carefully considered, along with measures to make participants physically and psychologically comfortable. Adverse reactions in these settings are rare, and far less dramatic than movies and TV would have you believe. There is a lot of variability in how people react to psychedelics, and two people taking the same drug, in the same setting, with the same therapy, are likely to describe their responses in different ways. What causes this great variability has largely been left unstudied. Recently, a systematic review of literature was conducted to examine some factors that might contribute to the variability in reactions.

Researchers combed through scientific journals to identify 14 separate studies that reported on experiences under the influence of psychedelics. In this review, the researchers only focused on classic psychedelics, which include psilocybin, LSD, mescaline, and ayahuasca/DMT. They found some important factors that predicted how individuals might respond to these substances, ranging from genetic traits, to personality aspects, and finally the emotional and mental state that people found themselves in prior to taking the drug (often called the “set” or “mindset’). The authors also note that of the 14 studies they included, the median year of publication was in 2018. This highlights just how new the topic is and how much more there is to be explored.

The most meaningful biological predictor they found was in how individuals’ brains processed serotonin.  Specifically, they assessed the sensitivity of participants’  5-HT2A receptor (this sensitivity is called its “binding potential”). Since this is the receptor that psychedelic drugs interact with, it makes sense that having a more sensitive receptor may change how people react to psychedelics. In terms of what this means for effects, people with increased binding potential experienced longer peak effects, a quicker and more drastic return to normal, and reported more mystical experiences. Mystical experiences are correlated with more profound and beneficial outcomes, so this biomarker may give a clue as to who is most likely to benefit from psychedelic treatment. It’s also noteworthy that biological sex was not associated with different reactions. While one study reported that females were more likely to have adverse effects, the bulk of the research they examined showed no difference between males and females. This is important to point out because psychedelic research has often tended to be skewed towards male participants.

As far as personality is concerned, the trait that showed the most drastic differences in psychedelic effects was absorption. Absorption is the capacity for one to be involved with their imagination, fantasy, and mental imagery. Individuals who tested high in absorption reported more mystical-type experiences, greater ego-dissolution, and increased color and vividness in the visual aspects of their experiences. This trait has been shown to be related to 5_HT2AR binding potential, further strengthening the backbone that these theories are being built upon.

Openness to experience, a personality trait that has also been shown to be highly related to absorption, was correlated to similar positive effects and negatively related to adverse reactions. Interestingly, psychedelic drugs have been reported to increase the dimension of openness in people’s personalities. Finally, acceptance, or a person’s ability to take in and process the reality of a situation without resisting or attempting to change it, was associated with more of the positive effects of psychedelics. If you’re interested in getting an intro to how you score on some of these traits, here is a good place to start.

Another important predictor of psychedelic effects is the mood and expectations of a person directly before taking the drug. This is commonly referred to as the “set” in “set and setting” that have long been touted as necessary for ensuring positive outcomes with psychedelic use. Individuals who approached a psychedelic experience with apprehension, confusion, and/or distress were more likely to have an adverse reaction and less likely to have mystical-type effects. Those who started in a state of surrender, a readiness to accept the effects of the drug, were more likely to experience ego-dissolution and have mystical-type experiences. In addition, those who reported taking the drug for spiritual purposes, and those who set clear intentions for what they wanted to gain from the experience, were more likely to have positive effects.

These findings represent the tip of the iceberg for predicting how a psychedelic experience will go. There are many more factors, both biological and personal, that are likely to be uncovered with more research. All of the major categories these markers fall into, physical traits, personality traits, and personal states, seem to overlap at one point or another. The prominent predictors of positive outcomes all appear to be related with one’s ability to let go of apprehensions and be completely immersed in the experience. Those who resist or don’t know what they want from psychedelics tend to have less enjoyable and more challenging episodes. As this body of research grows, it is important for clinicians and therapists to incorporate new information into deciding who is right for psychedelic therapy and treatment.


  • Everyone reacts to psychedelics differently, based on many biological, personal, and circumstantial factors.

  • Differences in a receptor in the brain that processes serotonin seem to point towards different reactions from psychedelic medicines.

  • The “set and setting”, or the physical setting and the mindset of a person going into a psychedelic experience are important in ensuring positive experiences for all users.

  • Most research shows that people who are able to let go of apprehension and become immersed in the experience without resisting tend to have more positive reactions.

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