Antidepressant effects of psychedelics may be overstated in some clinical trials

A meta-analysis of studies examining the antidepressant effects of psychedelics has found that the strength of these effects depends heavily on the design of the study. For example, studies that used active drugs as a placebo did not report antidepressant effects, while those comparing psychedelic treatments to waitlist control groups typically reported large effects. The study was published in the Journal of Affective Disorders.

Psychedelics are a class of psychoactive substances known for producing profound changes in perception, mood, and cognition. These substances primarily act on serotonin receptors in the brain. Common psychedelics include LSD (lysergic acid diethylamide), psilocybin (found in magic mushrooms), DMT (dimethyltryptamine), and mescaline (a compound derived from peyote and other cacti).

Scientific interest in psychedelics peaked in the 1950s and 1960s, but legal restrictions imposed in the late 1960s halted most research. In recent years, however, interest has resurged, with studies investigating the therapeutic potential of psychedelics for mental health conditions such as depression, post-traumatic stress disorder, and anxiety—particularly anxiety related to terminal illness.

According to study author Jia-Ru Li and colleagues, research on the antidepressant effects of psychedelics has yielded mixed results. While some studies report strong antidepressant effects, others find no effect at all. The researchers hypothesized that this inconsistency might be explained by differences in study design, especially in how the psychedelic treatment was compared to control conditions. To test this hypothesis, they conducted a meta-analysis.

The researchers searched several clinical trial databases for studies that evaluated the antidepressant effects of psychedelic drugs in adults diagnosed with depression or with a life-threatening illness accompanied by depressive symptoms. Eligible studies had to use standardized, validated rating scales to measure depressive symptoms.

The analysis considered five types of study designs:

• Studies using a non-active drug as a placebo (a non-psychedelic substance with no antidepressant properties);
• Studies using an active drug as a placebo (typically very low doses of psychedelics);
• Pre-post studies without a control group, comparing participants’ depressive symptoms before and after treatment;
• Studies using a waitlist control group, where control participants receive the treatment at a later time;
• Fixed-order designs, in which participants first receive a placebo (without knowing it is a placebo) and then receive the psychedelic treatment in a subsequent phase.

The final analysis included 21 studies: 11 tested the effects of psilocybin, 5 examined MDMA, 3 studied ayahuasca, and 2 assessed LSD.

The results showed that the apparent antidepressant effects of psychedelics varied depending on the type of study design. Studies that used a non-active placebo reported large or medium antidepressant effects for psilocybin and MDMA.

In contrast, studies that used an active placebo reported no antidepressant effects. Studies without control groups and those with waitlist controls also reported large effects for psilocybin. Studies on ayahuasca showed large antidepressant effects, while LSD showed notable effects only in the study using a non-active placebo.

“The antidepressant effects of psychedelics may be overestimated in studies with pre-post single-arm, non-active drugs as placebo, and waitlist-control designs. Restricted sample size, difficulty with establishing blinding for participants, and over expectancy limit the estimation of the antidepressant effect of psychedelic-assisted therapy,” the study authors concluded.

The study sheds light on possible factors producing the discrepancies in reported antidepressant effects of psychedelics. However, it should be noted that the number of studies included in this meta-analysis is relatively small given the number of psychedelics examined and the number of different study designs. This is especially the case for ayahuasca and LSD.

The paper, “The association between study design and antidepressant effects in psychedelic-assisted therapy: A meta-analysis,” was authored by Jia-Ru Li, Kuo-Tung Chiang, Yu-Chen Kao, Chia-Ling Yu, Fu-Chi Yang, Chih-Sung Liang, and Tien-Wei Hsu.