In a recent study published in NPJ Mental Health Research, scientists seek to uncover the role of subjective experiences such as dissociation and mystical states in the treatment outcomes of treatments involving psychedelic drugs such as ketamine and psilocybin. I did. The researchers found that subjective efficacy had a small impact on improving treatment for conditions such as depression and substance use disorders, and that psilocybin’s effects were slightly stronger than ketamine. The results of this study suggest that these subjective experiences may play a limited but important role in the effectiveness of psychedelic treatments.
Although psychedelics were once associated primarily with recreational drug use, their potential therapeutic effects have recently gained attention. Both ketamine, a dissociative anesthetic, and psilocybin, the active compound in magic mushrooms, have shown promise in treating conditions such as depression and substance use disorders.
These treatments differ from traditional drug therapies because they often result in deeply subjective experiences during use. Some researchers and clinicians believe that these experiences may contribute to the therapeutic efficacy of these drugs. However, the exact relationship between subjective efficacy and clinical benefit remains unclear.
“Psychedelic science is an emerging field of research in the fields of psychiatry and pain medicine that has received significant attention in recent years. In particular, trials of the classic psychedelic psilocybin and the dissociative drug ketamine have shown large effect sizes; “We have very promising results with a very rapid onset of effect (after one or several doses),” said study author and medical student Jack Dahan. Amsterdam University Medical Center.
“What makes these drugs particularly interesting is that each psychedelic compound produces very different subjective experiences, or ‘trips.’ The effects of these drugs are often attributed to the psychological effects of subjective experience, but the true role of subjective effects and differences between classes of psychedelics remained unclear. ”
To investigate the association between subjective efficacy and treatment outcome, researchers conducted a systematic review and meta-analysis. This method allowed us to combine data from multiple studies and examine overall trends in the studies. “There was a lack of meta-analyses (with hard data) on this topic,” Dahan said. “That’s why we decided to conduct this study.”
They searched electronic databases such as PubMed, EMBASE, and Web of Science for studies focused on the use of ketamine and psilocybin in the treatment of depression and substance use disorders. Studies had to meet several criteria to be included. That is, it was a human trial, had to report the effect of the treatment on the condition being studied, and provide quantitative data on the correlation between subjective effects and treatment outcome. The researchers included only randomized controlled trials or open-label trials that are commonly used to evaluate drug treatments.
They reviewed a total of 23 studies, of which 15 focused on ketamine and eight focused on psilocybin. These studies included patients receiving treatment for depression or substance use disorders, and the subjective effects experienced by the patients were assessed using the Clinician-Administered Dissociative State Scale (CADSS) for ketamine and the Clinician-Administered Dissociative State Scale (CADSS) for psilocybin. It was measured using tools such as questionnaires designed to capture mystical experiences.
Meta-analyses revealed a moderate role of subjective efficacy in mediating treatment outcomes for both ketamine and psilocybin. However, the strength of the correlation differed between the two substances and the condition being treated.
In the case of ketamine, the correlation between subjective effects and treatment outcome was found to explain approximately 5–10% of the drug’s effectiveness in treating depression. In contrast, for psilocybin, the correlation was stronger and accounted for approximately 24% of the treatment effect. This suggests that psilocybin’s subjective effects, such as mystical experiences, may be more directly related to its therapeutic effects than ketamine’s dissociative effects.
“We imagined in advance that ketamine would show a larger mediating effect,” Dahan told SciPost. “This may be due to the nature of ketamine’s dissociative effects themselves, or the fact that their effects are short-lived, ranging from 30 minutes to an hour, whereas psilocybin’s effects remain noticeable for hours to days after a treatment session. It might be something.”
The researchers also found differences between the symptoms they treated. In both ketamine and psilocybin studies, the correlation between subjective efficacy and treatment outcome was stronger for substance use disorders than for depression.
Specifically, in the treatment of substance use disorders, subjective efficacy accounted for up to 54% of treatment improvement for ketamine and 60% for psilocybin. This may indicate that psychological or perceptual changes brought about by these drugs may play a more important role in the treatment of drug use disorders compared to depression.
“Although this meta-correlation analysis on the role of subjective effects and treatment outcome of ketamine and psilocybin in depression and substance use disorders is exploratory and the results should be considered with caution, the mediating role of subjective state psilocybin compared to ketamine, especially when we limit the analysis to depression,” Dahan explained.
However, as with all research, there are some caveats to consider.
First, this analysis was based on a relatively small number of studies, particularly those related to substance use disorders, with only four studies included. This limits the generalizability of the results and further research is needed to confirm these results in a larger and more diverse population.
Second, this result does not prove that the subjective experience caused by the drug is directly involved in the therapeutic effect. Both experience and benefit can occur at the same time because the same brain processes are triggered, rather than one directly causing the other.
“In this study, we matched correlation coefficients,” Dahan said. “Thus, our results cannot positively judge causality and suggest that the subjective effect is an epiphenomenon arising from activated brain networks with pharmacodynamic properties similar to the treatment effect. We cannot rule that out with certainty.”
In the future, the researchers suggest considering other approaches to better understand the role of subjective effects. One possible approach is to study patients who undergo these treatments under general anesthesia and experience no subjective effects to see if the treatment results are the same. Additionally, future studies could investigate whether reducing the strength of subjective effects, for example by using a lower dose of the drug, affects overall efficacy.
“The role of subjective effects remains interesting,” Dahan says. “Future research would like to further elucidate the role of the subjective effects of psychedelics in mediating treatment outcomes, possibly taking into account the role of psychotherapy and performing different types of analyses, such as PKPD analyses.” We also hope to explore the effects of ketamine on opioid receptor sites and the role of opioids in general in depression and other mood disorders.”
The study, “Meta-correlations of the effects of ketamine and psilocybin induced subjective effects on treatment outcome,” was authored by Jack DC Dahan, David Dadiomov, Tijmen Bostoen, and Albert Dahan.
