This study questions recent claims about the rapid effectiveness of psychedelic drugs for treating depression. Among all psychedelics, only high-dose psilocybin showed greater effectiveness than the placebo in antidepressant trials and outperformed escitalopram.
Researchers from National Taiwan University, I-Shou University, and the National Defense Medical Centre conducted a study using a network meta-analysis of published randomized controlled trials to compare the effects of psilocybin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and ayahuasca with escitalopram in individuals with depressive symptoms.
Their findings revealed that, among all the psychedelics tested, only high-dose psilocybin demonstrated greater effectiveness than escitalopram.
To ensure accurate comparisons, the researchers analyzed the placebo responses separately in both the psychedelic and antidepressant trials. They found that the placebo response in psychedelic trials was lower than that in antidepressant trials. Furthermore, the effect size of high-dose psilocybin on depressive symptoms was found to be modest, which contrasts with previous claims suggesting a more substantial improvement.
Past research has suggested that psychedelics provide rapid and substantial antidepressant effects, contrasting with the slower and more modest efficacy of traditional antidepressants. A meta-analysis published in 2023 reported that the standardized mean difference of psychedelics for depression reduction ranged from 1.37 to 3.12, which are considered large effect sizes.
In contrast, the standardized mean difference in antidepressant trials is approximately 0.3, indicating a small effect size and a more gradual onset of therapeutic benefit. However, this study published in BMJ challenges the perceived breakthrough of psychedelics’ antidepressant effects, suggesting that their efficacy may be more modest than previously reported.
Prof. Yu-Kang Tu from National Taiwan University, the senior author of the study, stated, "Conducting fully blinded psychedelic trials remains challenging. If patients become aware of being given a placebo, this may lead to an overestimation of the antidepressant effects of psychedelics. To address this, we analyzed placebo responses separately in psychedelic and antidepressant trials, minimizing bias and providing a clearer assessment of psychedelics' efficacy compared to placebo responses in antidepressant trials."
Dr. Tien-Wei Hsu from I-Shou University, the first author of the study, stated, “We do not deny the antidepressant effects of psilocybin. Through our analysis, high-dose psilocybin still demonstrated superior antidepressant efficacy compared to escitalopram."
Associate Professor Chia-Kuang Tsai from the National Defense Medical Centre, the co-first author of the study, stated, "However, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and low-dose psilocybin did not show significantly greater efficacy than placebo responses in antidepressant trials."
Dr. Chih-Sung Liang from Tri-Service General Hospital Beitou Branch, the corresponding author of the study, stated, “Through evidence-based analysis, we can determine the actual efficacy of a drug by quantifying the additional therapeutic benefit it provides beyond the placebo effect.”
Prof. Yu-Kang Tu’s email address: yukangtu@ntu.edu.tw