Are Psychedelics More Effective Than Antidepressants?

By Irene Yeh 

Psychedelic-assisted therapy (PAT) has gained a reputation as being more effective than traditional antidepressants (TAD) for treating depression, particularly for patients who have not responded well to TADs. However, the effectiveness of these treatments may depend on whether studies are open-label, where patients are aware of their assigned treatment—or blinded, where patients are unaware.  

To determine the effectiveness of TAD and PAT for major depression treatment, a team of researchers from University of California San Francisco, University of California Los Angeles, and Imperial College, London compared results from psychedelic therapy trials with results from an open-label TAD trial where the patients knew they were receiving an antidepressant (JAMA Psychiatry, DOI: doi:10.1001/jamapsychiatry.2025.4809). By analyzing both groups under unblinded circumstances, potential benefits from the effects associated with patients knowing their treatment are equal. 

Difference Between Blinded and Unblinded 

In clinical trials, patients are ideally “blinded” to receiving an active treatment or a placebo. However, some patients can guess their treatment based on side effects—called functional unblinding—which can make a treatment seem more effective than it actually is and potentially influence results. In PAT trials, 90-95% of participants can correctly identify their treatment due to the strong side effects of psychedelics, even when a placebo is used. In comparison to TAD trials, about 63% of participants guess correctly. 

To date, only one clinical trial has directly compared PAT (psilocybin) with a TAD (escitalopram). The study found no difference between the two treatments on its main outcome measure, but PAT showed significant improvement in secondary depression measures. This mixed outcome has led to debate on how reliable this study truly is. 

Because TAD trial participants may not figure out if they’ve received an active drug or a placebo, it makes it difficult to compare them with psychedelics. Comparing PAT and TAD trials where patients know what they are taking offers more equal comparison. 

Database Search and Comparisons 

The team searched PubMed’s database to identify trials of major depressive disorder in adult patients (ages 18 to 65). They included studies that used either TADs in open-label trials or a blinded or open-label PAT (e.g. lysergic acid diethylamide, psilocybin, mescaline, San Pedro, peyote, 5-methoxy-N,N-dimethyltruptamine, or ayahuasca). Studies conducted in inpatient settings or involving patients with psychotic depression or substantial comorbidities were excluded, but an exception was given for comorbid anxiety since it is a frequent co-occurrence with depression. Augmentation and combination trials were also excluded, as well as trials with run-in periods, the period between recruitment and randomization of a clinical trial. However, data from run-in periods were included as open-label TADs if the run-in period met all inclusion criteria, such as the open-label phase of a discontinuation trial. Articles were independently reviewed for inclusion by two research team members, depression scores were extracted, references were checked for additional trials, and study authors were contacted when data were missing. 

Out of 619 retrieved records, 38 met inclusion criteria. Among the 38, only 24 trials had the required variables, including 16 open-label TAD and eight PAT trials. In the PAT trials, six were formally blinded and two were open-label. The data were analyzed using the Bayesian and frequentist models. Researchers focused on how much patients’ depression scores changed from start to end of study. To do this, they combined results from many studies and used methods that account for differences between them, such as the use of different depression rating scales.  

Contrary to the researchers’ expectations, the results showed that there was no significant difference in effectiveness between TADs and PAT. The difference was only about .3 Hamilton Depression Rating Scale (HAM-D) units, according to both Bayesian and frequentist estimates. This finding remained consistent across different sets of studies that were analyzed. 

Open-label TAD trials showed better outcomes than blinded treatment. This finding is consistent with the researchers’ premise that TADs can be effectively blinded, thus blinding should lead to a difference. But PAT is effectively always open-label, so formal blinding makes no difference. The estimated difference between open-label and blinded for TADs was .85 HAM-D units using the Bayesian model and 1.29 HAM-D units in the frequentist model. Both models showcase that blinding was not clinically meaningful. 

Meta-analyses of TADs for treating depression have shown about 2.4 points of improvement on the HAM-D scale compared to placebos. Due to the small difference in improvement, some researchers have questioned the effectiveness of these medications. PAT has shown a mean effect of approximately 7.3 HAM-D points. With almost a 5-point difference, PAT appears to be a better treatment option than TADs.  

But these results may be misleading. Firstly, open-label TADs tend to work a little better than blinded treatment. This could be influenced by a patient knowing their assigned treatment, including positive expectancy. Secondly, placebo responses in PAT trials are considerably lower—about four points lower than in TAD trials, according to one analysis—which makes the treatment look more effective by comparison. The team also speculates that the “know-cebo” effect (the disappointment patients feel when they realize they are in the control group) could also influence placebo suppression in PAT trials. Consequently, about 55% of PAT’s apparent benefit may come from poor outcomes in the placebo group rather than strong improvements in the treatment groups. In some cases, placebo patients in PAT trials got worse, whereas TAD trials showed improvement in placebo groups. 

Limitations to Consider 

Some PAT trials exclusively recruited patients with non–treatment-resistant depression (TRD) while no TAD trial focused on TRD. Another key difference is that PAT trials measured outcomes much earlier than TAD trials, which may have influenced PAT to appear more effective. Additionally, PAT participants were more likely to be from a higher education background and there were fewer minorities, indicating bias in the results.  

There were also issues related to expectations and blinding. Most PAT trial patients can correctly guess if they’ve received active treatment. In contrast, open-label TAD trials had no uncertainty because patients knew exactly what they were taking. Furthermore, expectations differ, even when both treatments were effectively unblinded. PAT often receives more positive attention from the media than TADs, which could lead to patients with expectations of better results and thus influence outcomes. 

Using two HAM-D models may have also introduced minor inconsistencies, although overall conclusions stayed the same when only one common scale was used. For one part of the analysis comparing blinded and open-label TAD trials, the researchers relied on data from a separate meta-analysis with slightly different criteria, meaning there could be hidden differences—such as patient severity or how participants were selected—that may affect the results.  

The research team only examined symptom reductions and did not fully consider side effects and improvements in daily functioning. The analysis also only looked at overall changes within patients and did not include the direct effects of the treatments, placebo effects, and natural improvement over time. As such, the study cannot separate how much of the improvement is due to the treatment rather than the aforementioned factors. 

While blinding made a difference for TADs trials, it did not for PAT trials, which confirms that PAT trials are as effective as open-label. The results of the study go against the growing popularity and hype surrounding psychedelic use to treat depression, but this does not mean PAT is ineffective. More importantly, it can still be a treatment option for patients and their healthcare provider to consider.