Recent research published in JAMA Psychiatry This suggests that psychedelic therapy may not be significantly more effective than standard antidepressants in treating depression when compared under similar conditions. The findings provide evidence that the impressive results seen in early psychedelic trials may have been influenced by study design rather than the unique chemical properties of the drugs themselves. This study helps clarify expectations for new mental health treatments and highlights the importance of fair comparisons in medicine.
Psychedelic therapy combines psychological support with the supervised use of mind-altering substances like psilocybin, the active ingredient in “magic” mushrooms. Patients typically undergo a preparatory therapy session before taking the drug in a controlled clinical setting. You will then attend follow-up sessions to help you process the experience.
Scientists conducted this study to address a major methodological problem in psychedelic research known as functional blinding. In standard clinical trials, neither patients nor doctors know who will receive the real drug and who will receive an inert placebo. This blinding process helps prevent patient expectations from influencing the results.
However, functional unblinding occurs when the physical or psychological effects of a drug are so obvious that it is easy to infer whether the patient received the actual treatment. Because psychedelic drugs cause severe changes in perception, nearly everyone who took a psychedelic drug in a trial knew that they were not receiving a placebo. This complete lack of mystery undermines standard testing procedures used in medical research.
This lack of blinding tends to exaggerate the perceived benefits of the drug. Patients who realize they have been given an active psychedelic drug often experience an increase in hope and positive expectations. At the same time, patients often experience deep disappointment when they realize they have been given a placebo, which can suppress their natural improvement.
“Functional unblinding, or ensuring that patients are aware of who receives a placebo and who receives a psychedelic in a formally blinded trial, is a central methodological issue in psychedelic trials. Lack of blinding introduces some bias. “While there is agreement in the field that this bias is significant, there is disagreement about the magnitude of this bias,” said study author Balázs, a postdoctoral clinical data scientist in the UCSF Translational Psychedelic Research Program. Szigeti said.
To solve this problem, scientists sought to compare treatments on a level playing field by comparing open-label trials of psychedelic therapy and antidepressants. This approach allows researchers to measure how both treatments work when patients are fully aware of their medications.
“Our reasoning is that psychedelic therapy is virtually always open-label (i.e., patients know what treatment they are receiving), making it a fair comparison with other open-label interventions,” Szigeti said.
To conduct this study, the researchers performed a meta-analysis. This is a statistical method that combines data from multiple independent studies to identify broader trends. They searched medical databases for clinical trials treating adults with major depressive disorder. They specifically looked for trials that used either open-label standard antidepressants or psychedelic therapies.
Traditional medicines included common tablets prescribed daily, such as escitalopram and fluoxetine. Psychedelic interventions included mind-altering substances such as psilocybin, LSD, and ayahuasca. The final analysis included 24 clinical trials that met our rigorous criteria.
This dataset consisted of 16 open-label antidepressant trials involving 7,921 patients and 8 psychedelic therapy trials involving 249 patients. Scientists extracted depression severity scores from each study and standardized them using a common measure known as the Hamilton Depression Rating Scale. By converting all the data into a single scale, researchers were able to directly compare the improvement in symptoms reported by both groups.
The researchers used advanced statistical models to estimate the average change in depressive symptoms. This change was measured from the start of treatment to the primary endpoint of each trial. The researchers found no significant difference in symptom improvement between the two treatments.
Both psychedelic therapy and open-label antidepressants led to reductions in depression scores. The statistical model estimated that the difference in effectiveness between the two interventions was a fraction of the points on the depression scale. This negligible difference suggests that, given competitive conditions, psychedelic drugs are about as effective as conventional drugs.
“When I hypothesized before collecting the data, I wanted to be a psychedelic hero and show that psychedelics are still better than open-label antidepressants. That could be the basis for a strong case for the superiority of psychedelics,” Szigeti told SciPost. “While our results weren’t quite the opposite – we found no difference, rather than an antidepressant being better – we were surprised and disappointed after the analysis was put together.”
The scientists also investigated the effects of blinding on both types of treatment. For standard antidepressants, patients who knew they were taking the drug showed slightly greater improvement than patients in blind trials. This finding provides evidence that simply knowing that you are receiving treatment increases its effectiveness.
However, when it comes to psychedelic trials, researchers found no difference in results between formally blinded and open-label trials. This supports the idea that formal blinding in psychedelic research does not work. In any case, the drug’s powerful effects effectively unblind the patient. As it turns out, the large benefits of previously reported psychedelic drugs appear to be due in part to the poor performance of control groups in blinded trials.
If a disappointed placebo patient fails to improve, the active drug looks much better by comparison. Scientists call this phenomenon the “nowcebo” effect, which occurs when patients realize they’ve missed out on an experimental treatment. In some previous psychedelic trials, patients in the placebo group actually experienced worsening depression due to this disappointment.
Although these findings adjust expectations regarding symptom relief, it is important not to completely dismiss psychedelic therapy. The researchers note that their study only measured reductions in core depressive symptoms. Other potential benefits, such as improved function in daily life or differences in side effects, have not been evaluated.
“Our main finding is that patients’ improvement is the same after psychedelic therapy and traditional antidepressants when they know they are receiving active treatment,” Szigeti explained. “This finding does not mean that psychedelic drugs are ineffective, only that they are less effective than conventional antidepressants. These should also be understood as ‘average’ effects. Some patients will still benefit more from conventional antidepressants, while others will benefit more from psychedelic therapy.”
Some previous research suggests that standard drugs can cause emotional blunting and sexual dysfunction, while psychedelic drugs may help patients process emotions more deeply. These different side effect profiles are difficult to compare across a wide variety of trials. Psychedelics may offer an alternative option for patients who do not respond adequately to standard daily medications.
“We received a lot of criticism for only comparing symptom reduction as measured by classic depression scales,” Szigeti noted. “It is true that psychedelic therapy may result in better functional outcomes with fewer side effects. Unfortunately, data on these factors are heterogeneous and nearly impossible to compare across interventions.”
This study also had some limitations regarding matching data. Psychedelic trials often involve patients with treatment-resistant depression, which can make it difficult to treat the condition in the first place.
Additionally, the measurement timelines were different, as antidepressant clinical trials typically follow patients for about eight weeks. Psychedelic trials, on the other hand, typically measure results after about three weeks.
Looking ahead, scientists plan to continue investigating how patient expectations shape mental health treatment. “We plan to conduct a follow-up study comparing patient improvement after blinded antidepressant and psychedelic therapy,” Szigeti said. “More broadly, we are working on quantitative evaluations of the impact of blinding in both treatment and placebo groups for a variety of psychiatric disorders and interventions. My intuition is that the variation is much greater than the field assumes. Only time will tell.”
The study, “Psychedelic therapy and antidepressants for the treatment of depression under non-blinded comparable conditions: A systematic review and meta-analysis,” was authored by Zachary J. Williams, Hannah Barnett, and Balázs Szigeti.
