In a recent study published in npj Mental Health Research, scientists sought to clarify the role of subjective experiences, such as dissociation and mystical states, in the therapeutic outcomes of treatments involving psychedelics like ketamine and psilocybin. They found that subjective effects had a modest influence on therapeutic improvements in conditions like depression and substance use disorders, with the impact of psilocybin being somewhat stronger than that of ketamine. The findings suggest that these subjective experiences might play a limited, but not insignificant, role in the efficacy of psychedelic treatments.
Psychedelics, once primarily associated with recreational drug use, have recently gained attention for their potential therapeutic effects. 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 medications because they often produce profound subjective experiences during their use. Some researchers and clinicians believe these experiences might contribute to the therapeutic effects of these drugs. However, the exact relationship between the subjective effects and clinical benefits remains unclear.
“Psychedelic science is an emerging research area in the field of psychiatry and pain medicine that has gained much attention in the last couple of years. Trials on, among others, the classical psychedelic psilocybin and the dissociative drug ketamine have produced very promising results with large effect sizes and very rapid onset of effect (after one or a few doses),” said study author Jack Dahan, a medical student at Amsterdam University Medical Center.
“What makes these drugs especially intriguing is that each psychedelic compound produces very distinct subjective experiences or ‘trips.’ The effect of these drugs is often attributed to the psychological impact of these subjective experiences, but the true role of subjective effects and differences between classes of psychedelics remained unclear.”
To investigate the link between subjective effects and therapeutic outcomes, the researchers performed a systematic review and meta-analysis. This method allowed them to combine data from multiple studies to examine overall trends in the research. “Meta-analyses on this topic (with hard data) were lacking,” Dahan said. “That is why we decided to perform this study.”
They searched electronic databases such as PubMed, EMBASE, and Web of Science for studies that focused on the use of ketamine and psilocybin to treat depression or substance use disorder. To be included, the studies had to meet several criteria: they had to be human trials, report on the effects of the treatment on the condition being studied, and provide quantitative data on the correlation between subjective effects and therapeutic outcomes. The researchers only included randomized controlled trials or open-label studies, which are commonly used to evaluate drug treatments.
In total, they reviewed 23 studies, 15 of which focused on ketamine and 8 on psilocybin. These studies included patients being treated for either depression or substance use disorder, and the subjective effects they experienced were measured using tools such as the Clinician-Administered Dissociative States Scale (CADSS) for ketamine and questionnaires designed to capture mystical experiences for psilocybin.
The results of the meta-analysis revealed that subjective effects do have a modest role in mediating the therapeutic outcomes of both ketamine and psilocybin. However, the strength of the correlation varied between the two substances and the conditions being treated.
For ketamine, the correlation between subjective effects and therapeutic outcomes was found to explain about 5-10% of the drug’s effectiveness in treating depression. In contrast, for psilocybin, the correlation was stronger, accounting for around 24% of the therapeutic effect. This suggests that psilocybin’s subjective effects, such as mystical experiences, might be more directly related to its therapeutic benefits than the dissociative effects of ketamine.
“Beforehand, we imagined that the mediating effect of ketamine would show to be greater,” Dahan told PsyPost. “This may be due to the very nature of the dissociative effects of ketamine or due to the fact that its effects are short-lived—30 minutes to an hour—while psilocybin’s effects remain noticeable for hours to days after the treatment session.”
The researchers also found differences between the conditions being treated. In both ketamine and psilocybin studies, the correlation between subjective effects and therapeutic outcomes was stronger for substance use disorder than for depression.
Specifically, in substance use disorder treatments, the subjective effects accounted for up to 54% of the therapeutic improvement for ketamine and 60% for psilocybin. This may indicate that the psychological or perceptual changes brought about by these drugs play a more significant role in treating substance use disorder compared to depression.
“Although this meta-correlation analysis on the role of subjective effects of ketamine and psilocybin versus therapeutic outcome in depression and substance use disorder is exploratory and the results should be considered with caution, it points to the direction that the mediating role of subjective states is greater in psilocybin compared to ketamine, especially when restricting the analysis to depression,” Dahan explained.
But as with all research, there are some caveats to consider.
First, the analysis was based on a relatively small number of studies, especially for substance use disorder, where only four studies were included. This limits the generalizability of the findings, and more research is needed to confirm these results in larger and more diverse populations.
Second, the results do not prove that the subjective experiences caused by the drugs are directly responsible for the therapeutic benefits. It is possible that both the experiences and the benefits co-occur because the same brain processes are being triggered, rather than one directly causing the other.
“In this study, we collated correlation coefficients,” Dahan said. “As such, our results cannot affirmatively determine causality. And, we cannot exclude with certainty that subjective effects are epiphenomena that arise from activated brain networks with similar pharmacodynamic properties as the therapeutic effects.”
Moving forward, the researchers suggest exploring other approaches to better understand the role of subjective effects. One possible approach is to study patients who receive these treatments while under general anesthesia, preventing them from experiencing the subjective effects, to see if the therapeutic outcomes are the same. Additionally, future studies could investigate whether reducing the intensity of subjective effects, for example by using smaller doses of the drugs, impacts their overall effectiveness.
“The role of subjective effects remains intriguing,” Dahan said. “In future research, we hope to further untangle the role of subjective effects of psychedelics in mediating therapeutic outcomes, possibly taking into account the role of psychotherapy and performing different kinds of analyses, such as PKPD-analyses. Furthermore, we hope to delve into the effect of ketamine at the opioid receptor site and the role of opioids in general in depression and other mood disorders.”
The study, “Meta-correlation of the effect of ketamine and psilocybin induced subjective effects on therapeutic outcome,” was authored by Jack D. C. Dahan, David Dadiomov, Tijmen Bostoen, and Albert Dahan.
