The Intricate Interaction Between Expectations and Therapeutic Outcomes of Psychedelic Agents

Expectations affect the course of many medical conditions, impacting key measures, including long-term mortality¹ and surgical outcomes.² Expectations account for a substantial proportion of the overall therapeutic effect of some pharmacological treatments; for example, up to 50% of the effectiveness of pain therapeutics may be expectation driven.³ Expectations can also be tempered by previous unsuccessful treatments and unfavorable encounters, diminishing therapeutic outcomes.³

Expectations are particularly important in relation to psychedelic drugs and 3,4-methylenedioxymethamphetmine (MDMA) because they may paradoxically serve both as potential confounding factors and as critical mediating factors in the mechanism of antidepressant action. The role of pretreatment expectations in relation to psychedelic treatment effectiveness and the potentially unique ability of these treatments to alter future expectations has profound clinical consequences that deserve special consideration when evaluating the place of psychedelic medications and MDMA in the treatment of mental (and other chronic) disorders. This discussion goes beyond the clinical trial limitations related to functional unblinding and a priori patient expectations associated with psychedelic agents reported elsewhere.⁴Rather, we focus on the more complex role expectations may play in relation to the mechanisms underlying psychedelic treatments’ putative effectiveness in treating psychiatric disorders. We offer a call to action for investigators to thoughtfully integrate longitudinal assessments of expectations into future studies. We believe that this information would not only provide a better understanding of how expectations are associated with treatment outcomes at various stages during treatment, but also afford insight into how these treatment effects could be successfully amplified in clinical settings.

Set, Settings, and Outcome Expectations

Two components are integral to the success of most psychedelic treatments currently being evaluated. The term set refers to the mindset of the patient, or the mental state a person brings to the experience, including their thoughts, mood, and expectations. Setting captures the physical and social environment in which the experience occurs. Extended preparatory sessions (lasting up to 8 hours in some protocols) designed to enhance the effectiveness and safety of these treatments provide an opportunity to both evaluate and alter a patient’s mindset and create de novo treatment expectations. For example, during these sessions, patients are informed of unique cognitive and sensorial changes that are associated with the psychedelic experience, and then it is suggested that these unique experiences will improve their mood. This information not only shapes an initial treatment expectation around the acute cognitive and sensorial changes, but also provides opportunities to foster an expectation of outcome (ie, if I have the experience, then I will get better; if I do not, then I will not). This factor must be acknowledged when attempting to interpret randomized controlled trials evaluating the effectiveness of psychedelic treatments.

Drug Actions and Resetting Expectations

In addition to the implications that pretreatment expectations may have for treatment response, recent studies suggest that expectations may be reset under the action of psychedelic drugs and MDMA treatments. Psychedelic and MDMA actions may drive the brain to reinterpret the world, potentially updating past beliefs and desires. Psychedelic drugs may alter the experience of reality and the way inferences of the world are made, realigning what is expected with what is perceived.⁵ Under the action of psychedelic drugs, the brain and its modulatory systems may be prone to reinterpret affective, sensory, and cognitive inputs in ways that reconcile mismatches between what is expected and what is perceived. Furthermore, they may enhance the imposition of new expectations—a mechanism potentially culminating at the extreme with the drugs’ hallucinatory effects.

Posttreatment Sessions and Reinforcing New Beliefs

Humans update beliefs about future outcomes dynamically based on novel events. In healthy conditions, updating of beliefs tends to be asymmetric, with an updating toward desirable outcomes (ie, the so-called good news/bad news bias). However, patients with depression lack this optimism bias and may have unfavorable expectations about future events. Shifting the process of updating beliefs toward positive expectations and desirable outcomes has been associated with clinical improvement following ketamine treatment.⁶ Thus, it is possible that these treatments may modify existing beliefs and expectations of future events. These new beliefs that such profound experiences are possible may be maintained outside of the drug experience, particularly if the experiences reinforce the expectations established during the preparatory sessions that suggested it could result in more sustained clinical benefits. The durability of the new beliefs may be cemented at the neural level through the drugs’ability to directly enhance metaplasticity (the plasticity of synaptic plasticity), as recently shown in mice⁷

In the case of psychedelic treatments, this metaplasticity may be further augmented during follow-up integration sessions that allow reinforcement of the new beliefs (Figure). The science of expectation, perception, and belief updating has yielded theories and procedures within which the roles of expectation on perception can be precisely quantified.⁸ Combining these advances with the resurgent clinical investigation of psychedelic drugs and MDMA may prove critical to understanding how expectations ultimately interact with treatments to generate overall clinical improvement. The importance of understanding the complex role that expectations have in relation to psychedelic treatments is further highlighted by recent concerns that the media hype surrounding psychedelic drugs may well be perpetuating and reinforcing pretreatment expectations of benefit and may complicate rigorous evaluation of treatment effectiveness.⁹

Figure. Interactive and Sequential Cycle of Psychedelic-Like Treatments.

The Figure illustrates multiple points in the treatment process where expectations can contribute to overall treatment responses. The treatment cycle includes preparatory sessions, drug (psychedelic drugs or MDMA [3,4-methylenedioxymethamphetmine]) treatment sessions, and integration sessions. Preparatory sessions provide an opportunity to assess and shape treatment and outcome expectations. The drugs may generate molecular events that directly interact, or unique cognitive or perceptual experiences that indirectly interact, with expectations, enhancing metaplasticity and allowing long-lasting cognitive changes and, ultimately, clinical improvements. Integration sessions allow for a reshaping of patients’ expectations that is likely facilitated by the enhanced plasticity induced by the drug treatment.

Conclusions

A careful longitudinal assessment of how patients’and clinicians’expectations at all stages of the therapeutic process may alter treatment response will be enlightening. It is difficult to separate expectations from true pharmacological effects for any treatment, and this is especially true for psychedelic drugs and MDMA, for which the profoundly subjective treatment effects cannot be blinded, and indeed likely underlie treatment effectiveness. Expectations can affect responses at every stage of psychedelic-assisted psychotherapy, and the drugs themselves may alter expectations and outcomes. We urge the field to include longitudinal and dynamic assessments of prior experiences and expectations (eg, using a visual analog scale¹⁰) during preparatory, treatment, and integration sessions of psychedelic-assisted psychotherapy This knowledge will not only allow for a more informed interpretation of clinical trial findings, but will also help optimize the treatment approach if psychedelic and MDMA treatments move forward in the clinic.