Reacción a "A study suggests that psychedelics are no more effective than antidepressants and confirms that the studies are not double-blind"

The article by Williams et al. analyzes the published scientific evidence through a rigorous meta-analysis on the treatment of major depression in outpatient settings, comparing the efficacy of commonly used conventional antidepressant drugs in clinical practice—such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)—with so-called psychedelic-assisted psychotherapy (PAP). This is not a common practice in Spain, but it has had strong support for more than five decades in other places, such as the United States, and has re-emerged in recent years as a novel treatment for depression. This type of therapy uses different psychoactive substances as tools to support psychological intervention, including amphetamine derivatives, LSD, plant and fungal alkaloids from Latin America (psilocybin, mescaline, peyote), and ayahuasca.

Previous studies had shown greater efficacy of PAP compared to placebo, but this article suggests that this difference may be partly explained by factors such as patient expectations or a reduced placebo response in psychedelic trials. This highlights—consistent with other recent work—the challenges in clinical trial design and bias control. For example, it is known that PAP trials often include more highly educated patients, who may be more receptive to these therapies (particularly in the United States), and that ethnic and racial minorities are underrepresented, which can bias results in favor of PAP. It could even be argued that psychedelic medicine receives more positive media coverage than antidepressant drugs, meaning that without proper double-blind design, results may be skewed toward greater apparent efficacy due to higher expectations surrounding PAP.

For all these reasons, this meta-analysis addresses the issue by comparing the effectiveness of both approaches under equivalent methodological conditions, in adult patients with major depression without comorbidity treated in outpatient settings. Overall, it is a study of good methodological quality, following PRISMA guidelines, and it combines Bayesian and frequentist statistical models, reinforcing its transparency and scientific rigor. It includes 24 clinical trials: 16 open-label antidepressant trials (7,921 patients) and 8 PAP trials (249 patients), of which only 2 are open-label (36 patients) and the other 6 use blinded methodology (213 patients). In addition, the authors explicitly account for several confounding factors, especially the issue of functional unblinding, which is particularly relevant in psychedelic studies due to the obvious subjective and adverse effects of these substances—even in formally blinded trials. This phenomenon can amplify differences between drug and placebo effects and effectively makes all PAP studies functionally open-label. Differences in baseline depression severity, treatment duration, and population type were also considered.

However, several important limitations remain, such as the small number of psychedelic trials and their heterogeneity: small and sometimes unrepresentative sample sizes, as well as methodological differences across studies included in the meta-analysis (e.g., follow-up duration or inclusion criteria). Moreover, the analysis focuses solely on the reduction of depressive symptoms, without considering key aspects such as adverse effects or long-term functioning. Finally, the authors relied exclusively on the PubMed database for their literature search, which, although comprehensive, may not include all relevant trials. All of this should be taken into account when interpreting the results.

Despite these limitations, the study’s conclusions appear to be supported by consistent data, confirming the absence of significant differences in depression improvement (using the 17-item Hamilton Depression Rating Scale and standardizing results across studies) between PAP and antidepressant use. This finding is particularly relevant because it contradicts the dominant narrative in the United States suggesting a clear and overly optimistic superiority of psychedelic-assisted therapy. In this regard, the authors convincingly argue that many previous studies may have overestimated the efficacy of PAP due to issues with study design and the integrity of blinding.

In terms of real-world clinical practice, this work suggests that traditional antidepressant drugs remain a valid first-line treatment option. The use of psychedelics may be promising, but there is still insufficient evidence to consider them superior to conventional antidepressant treatment. More robust studies are needed, with better control of blinding and bias, and with evaluation of clinically relevant long-term outcomes. Regarding existing evidence, this study does not deny that psychedelics may be effective, but it does question their apparent advantage over conventional treatments. This is highly relevant in a context of growing media and clinical interest in psychedelics, as it cautions against drawing premature conclusions. Additionally, in the Spanish context, the issue is less pressing, as the use of psychedelic-assisted psychotherapy remains very limited (although some clinical trials have been initiated), given that many of the substances involved are regulated and illegal in the country.