Meta-correlation of the effect of ketamine and psilocybin induced subjective effects on therapeutic outcome

Millions suffer from psychiatric conditions, and current antidepressants have limited and delayed efficacy, highlighting the need for alternative treatments. Psychedelics, including ketamine (non-classical) and psilocybin (classical), have shown promise in treating various psychiatric illnesses. These drugs induce psychoplastogenic effects, promoting neural plasticity. While their shared mechanisms are understood to some extent, the unique subjective effects of each psychedelic, perceived as meaningful by some users, are implicated as potential therapeutic mechanisms. The study aimed to quantitatively determine the magnitude of correlation between ketamine- and psilocybin-induced subjective effects and therapeutic improvements, comparing these effects between ketamine and psilocybin treatments. This is, to the researchers' knowledge, the first meta-correlation analysis on this topic.

Existing literature suggests that subjective effects of ketamine and psilocybin are crucial for their therapeutic effects, although this hypothesis is debated due to inconsistent findings across studies. Inconsistencies arise from differences in temporal dynamics between subjective effects and therapeutic outcome, use of insensitive measurement tools, and the apparent lack of clear dose-response relationships. Previous narrative reviews exist, but lack quantitative meta-analysis.

The researchers conducted a systematic literature search using PubMed, Embase, and Web of Science, retrieving 2049 unique papers. After applying inclusion and exclusion criteria (human studies, full-text availability, reporting on both treatment effects and subjective effects, providing quantitative correlation data, using RCTs or open-label studies, and focusing on ketamine, esketamine, or psilocybin for depression or SUD treatment), 23 studies were included (11 ketamine, 9 depression; 2 SUD; 8 psilocybin, 6 depression; 2 SUD). Studies with multiple overlapping datasets were consolidated, and two studies reporting no correlation were included in a secondary analysis with imputed zero correlation coefficients. Risk of bias was assessed using the Newcastle-Ottawa Scale and the revised Cochrane risk-of-bias tool. Random-effects meta-correlation analyses were performed using Comprehensive Meta-Analysis software. Subgroup analyses were conducted based on disease state (depression, SUD), trial type (RCT, open-label), and ketamine administration route (intravenous, intranasal).

The meta-analysis revealed a correlation between subjective effects and therapeutic benefit for both ketamine and psilocybin in treating depression and SUD. Pooled correlation coefficients were -0.310 for ketamine and -0.495 for psilocybin, translating to R² values of approximately 10% and 24%, respectively (5% and 24% respectively when including imputed zero values). Heterogeneity was observed across studies, with some showing R² values exceeding 50% while others found no correlation. Subgroup analyses indicated stronger correlations in SUD treatment compared to depression treatment for both ketamine (R² =54% vs 4%) and psilocybin (R² =60% vs 18%), although the SUD data stemmed from only four studies (two per treatment). The difference between ketamine and psilocybin was significant when including studies with imputed zero values (p=0.040), and when comparing depression studies alone, without imputation (p=0.0228). The pooled effect for SUD (four studies, 54 patients) was -0.740 (95% CI -0.862 to -0.539, I² = 12%, p=0.000).

The study’s findings suggest a modest role for subjective effects in mediating therapeutic outcomes of both ketamine and psilocybin, with a notably stronger effect for psilocybin, particularly in depression. The stronger correlation in SUD may be due to several factors, including the limited number of studies, noise in the data, or the inherent differences between SUD and depression. The use of diverse instruments for measuring subjective effects (CADSS, BPRS, MEQ) may have contributed to heterogeneity and the relatively low overall correlations. The short-lived nature of ketamine's subjective effects compared to psilocybin's longer-lasting effects might also explain the differences observed. Expectation bias, potentially influencing open-label studies more, didn't fully explain the observed discrepancies, as argued by the researchers. The impact of blinding was discussed with references to studies using ketamine under general anesthesia and a study using the nitric oxide donor SNP to reduce ketamine's effects. The researchers acknowledged the possibility that subjective effects are epiphenomena rather than causal factors.

This meta-analysis provides evidence for a modest role of subjective effects in mediating the therapeutic effects of ketamine and psilocybin, with psilocybin demonstrating a stronger correlation, particularly in depression treatment. Future research should focus on refining measurement tools to capture the full spectrum of subjective experiences, investigating the role of specific subjective experiences in mediating treatment outcomes, exploring the effects of combined psychedelic therapy with and without psychotherapy, and employing alternative study designs to minimize expectation bias.

The study’s limitations include the heterogeneity of studies, the relatively small number of studies, especially in subgroup analyses (e.g., SUD), and the use of diverse, not fully standardized, measures of both therapeutic outcome and subjective effects. The varying methodologies across studies and the possibility of non-linear relationships between subjective effects and therapeutic outcome might have influenced the results. Furthermore, the analysis cannot definitively establish causality.