New Study Reveals Suggestibility's Role In Antidepressant Effects Of Psilocybin Therapy

A new study led by Balázs Szigeti and with involvement of researchers Brandon Weiss, Fernando E Rosas, David Erritzoe, David Nutt and Robin Carhart-Harris found evidence of suggestibility predicting an antidepressant response for patients receiving psilocybin therapy.

The study aimed to understand the link between pre-trial expectancy, suggestibility and response to treatment in a previously conducted clinical trial comparing escitalopram and COMPASS Pathways' CMPS synthetic psilocybin, COMP360, in the treatment of 55 patients with Major Depressive Disorder (MDD.)

The researchers analyzed the association between expectancy and six depression/well-being related outcomes in the two arms. They also assessed suggestibility-outcome associations in both arms. Here’s what they found:

• Patients' expectancy for psilocybin was "significantly higher" as compared to escitalopram – what study PI Szigeti called in jest "the most unsurprising result of the year." 
• Confirming previous results, expectancy for escitalopram was associated with improved therapeutic outcomes to the traditional SSRI.
• Expectancy for psilocybin did not predict response to treatment with the psychedelic – "The big surprise" showed no expectancy-outcome association on none of the six scales.
• If anything, it showed some “negative expectancy,” like higher expectancy more associated with worse outcomes, or higher depression and lower well-being scores, Szigeti added.
• Pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm.
• In contrast with expectancy, higher suggestibility was strongly associated with better outcomes in the psilocybin arm, but not in the escitalopram arm.

Overall, researchers concluded that results suggest psychedelic therapy "may be less vulnerable to expectancy biases than previously suspected."

Nonetheless, they added, the relationship between baseline influence suggestibility and response to psilocybin therapy does imply that highly suggestible individuals "may be primed for response" to the psychedelic treatment.

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Why It Matters

Author Brandon Weiss says that finding evidence of expectancy predicting an antidepressant response in the study's escitalopram therapy arm but not in the psilocybin therapy arm is "at odds with the popular concern that response to psychedelic therapies could be significantly influenced by expectancy and placebo."

For context, the researcher explained that expectancy effects were in fact observed in a prior naturalistic ayahuasca research. The difference with the psilocybin study, he said, could owe to the controlled setting.

"It may be that in a controlled context, the nature of psilocybin therapy (physiologically and psychologically) outweighs the psychological influence of expectancy. People with lower [expectancy] don’t necessarily do worse, people with higher don’t necessarily do better," Weiss detailed.

In the publication's comments, authors note that high suggestibility "could imply elevated attunement to acute insights, and influence from therapy personnel such as therapist or clinical staff. Or higher susceptibility could make people more susceptible to placebo response."

Suggestibility has been linked to greater treatment response in Weiss et al previous works examining Shipibo-led ayahuasca ceremony.

Back to the study, participants had moderate-to-high expectancy regarding psilocybin therapy, so the data "cannot comment on whether people with 0 or very low expectancy do worse than people with moderate to high expectancy," but rather speaks of the comparison between moderate and high.

The study did have some limitations concerning statistical power, which made detection of "a smaller but still meaningful expectancy effect" for psilocybin therapy impossible.

Still, "it is still very likely (though formally untested) that the escitalopram expectancy effect is larger than the psilocybin expectancy effect," Weiss said, concluding that the finding "should open our minds to the possibility that expectancy cannot simply account for the compelling treatment effects we see with psychedelic therapies."

This was echoed by co-author Robin Carhart-Harris, who identified the above as the main finding. "It’s a result that demands we ask: If not expectancy, then what’s behind the impressive efficacy of psilocybin therapy?"

Psychedelics researcher Max Wolff, who did not participate in this study, also commented on the outcomes: "Unsurprising but important result: Among patients who (likely) prefer psilocybin but receive escitalopram, those who believe less in escitalopram benefit less from treatment. Among others who receive the desired psilocybin, strength of belief in psilocybin is not as important."

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Photo: Benzinga edit with photo by Acontent_creator and BCFC on Shutterstock.