A recent study examined the role of patient expectations in influencing the outcomes of treatments with psilocybin, a psychedelic substance, compared to escitalopram, a widely prescribed antidepressant. Contrary to what some might expect, the study did not find a significant link between patients’ expectations and their actual responses to psilocybin therapy. However, the study also indicates that individuals who are more suggestible might experience a greater benefit from this treatment.
The findings have been published in the journal Psychological Medicine.
Depression’s staggering global impact has intensified the search for more effective treatments. Despite the prevalent use of SSRIs, which have been shown to outperform placebos, their relatively modest effect sizes underscore the need for alternative treatments.
Psychedelic-assisted therapy has been spotlighted as a potentially groundbreaking approach, promising significant and enduring benefits to mental health within just a handful of sessions. But questions have been raised regarding the extent to which expectancy effects may be contributing to the positive outcomes observed in early trials.
Expectancy effects refer to the phenomenon where a person’s expectations about the outcome of a treatment can influence the actual outcome. This psychological effect is a component of the placebo effect, where belief in the efficacy of a treatment can lead to improvements in symptoms, regardless of whether the treatment has an active therapeutic ingredient.
Blinding is a methodological technique used in clinical trials to minimize biases, including expectancy effects. In a double-blind study, neither the participants nor the researchers know who is receiving the active treatment and who is receiving a placebo. This approach helps to ensure that the observed effects of the treatment are due to the treatment itself, rather than the participants’ or researchers’ expectations.
However, blinding is particularly challenging in psychedelic research because the distinct psychoactive effects of substances like psilocybin make it easy for participants to guess whether they have received the psychedelic or a placebo, potentially undermining the study’s methodological integrity.
The current study was motivated by a desire to rigorously assess the true efficacy of psychedelic treatments. By understanding how patients’ expectations and the unblinded nature of psychedelic experiences influence therapeutic outcomes, researchers can better discern the genuine effects of psychedelics from those influenced by psychological biases.
“My way into psychedelic research was to conduct a large placebo-controlled study on psychedelic microdosing,” explained first author Balázs Szigeti, a data scientist at UCSF’s Translational Psychedelic Research Program and an honorary affiliate at Imperial College’s Center for Psychedelic Research.
“There we found evidence that expectancy and unblinding effects are likely key drivers of positive outcomes. Given this finding it was natural to wonder if the same is true for large doses of psychedelics that are now used as experimental mental health treatment.”
In the current study, the researchers analyzed data collected during a phase 2, double-blind, randomized trial that included 55 individuals with moderate-to-severe major depressive disorder. Participants in the trial were randomly assigned to one of two treatment arms.
Those in the psilocybin arm received two doses of 25mg of psilocybin, administered three weeks apart, alongside six weeks of daily placebo capsules. Those in the escitalopram received two doses of 1mg of psilocybin (considered a non-therapeutic dose and thus acting as a placebo) three weeks apart, in addition to a daily regimen of escitalopram (10mg/day for the first three weeks, increasing to 20 mg/day for the final three weeks).
To gauge participants’ expectations regarding the efficacy of each treatment, two items were administered one day before the dosing days, asking participants to rate their anticipated improvement in mental health after receiving either escitalopram daily for six weeks or two full doses of psilocybin three weeks apart.
The researchers also assessed traits such as suggestibility and absorption at baseline. Suggestibility, or the tendency to accept and act on suggestions from others, was measured using the Short Suggestibility Scale (SSS). Absorption, a trait indicating a predisposition to experience altered states of consciousness, was evaluated using the Modified Tellegen Absorption Scale (MODTAS).
The participants were generally more optimistic about the outcomes of psychedelic therapy compared to escitalopram treatment. Despite this, the researchers found no significant relationship between patients’ pre-treatment expectations and their responses to psilocybin therapy. In contrast, they found that expectations did play a role in the outcomes of escitalopram treatment.
Furthermore, the researchers uncovered that individuals with higher suggestibility experienced more pronounced benefits from psilocybin therapy. This finding indicates that a patient’s susceptibility to suggestions and possibly their openness to the psychedelic experience can enhance the treatment’s effectiveness. This characteristic did not similarly influence responses to escitalopram, pointing to a unique interaction between suggestibility and psychedelic therapy.
“The lack of effective blinding and potentially large expectancy effects driven by the considerable hype around psychedelic treatments is a common criticism,” Szigeti told PsyPost. “However, in the first psychedelic randomized controlled trial that formally assessed expectancy, we did not find evidence for large effects, although at the same time we could not formally rule out some small expectancy effects.”
One significant limitation was the study’s reliance on a small sample size and non-validated expectancy measures, which might have constrained its capacity to detect nuanced effects of expectancy on treatment outcomes. Intriguingly, the researchers suggest the possibility of a “negative expectancy” effect, where higher expectations might lead to worse treatment outcomes for psilocybin therapy. This arises from observed data patterns that did not reach statistical significance but showed trends where higher expectancy could be associated with poorer responses.
Additionally, the absence of data regarding participants’ and assessors’ guesses about treatment allocation limited the assessment of blinding integrity, a crucial factor in evaluating the placebo effect’s influence on therapeutic efficacy.
Regarding the long-term goals for this line of research, Szigeti said he hopes to continue to address the methodological challenges posed by the psychoactive nature of psychedelics.
“Modern medical research is based on blinded placebo-controlled research, i.e. patients and assessors not knowing what the treatment is,” he explained. “However, with psychedelics the treatment is obvious given the strong psychoactive effect of the drugs. This is a fundamental tension in psychedelic research that raises questions such as how can we estimate the placebo component of psychedelic treatments, does it matter if these treatments are ‘unblindable,’ etc. My aim is to address these questions surrounding the tension between blinding and psychedelics.”
The study, “Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression,” was authored by Balázs Szigeti, Brandon Weiss, Fernando E. Rosas, David Erritzoe, David Nutt, and Robin Carhart-Harris.
