Review supports psilocybin efficacy but calls for more real-world research

06 May 2024 --- Researchers suggest that psilocybin is a more effective treatment for symptoms of depression than controls. They reviewed randomized controlled trials that compared the compound of “magic” mushrooms with controls, such as placebo, niacin (vitamin B) or microdoses of psychedelics.

The review found the most significant improvements for psilocybin treatment for patients with secondary depression — related to an underlying disease — instead of primary depression, self-reported scale rather than using a clinician-assessed scale, older age and previous use of psychedelics. 

At the same time, they note that “further research is needed to clarify the factors that maximize psilocybin’s treatment potential for symptoms of depression.” 

Dr. Paul Keedwell, consultant psychiatrist and fellow of the Royal College of Psychiatrists, welcomes the efficacy review of a single psilocybin dose to treat depression. “The results are impressive, with rapid improvement in most, and large effect sizes,” he says.

“Longer follow-ups would be welcome, and more work should be done on optimal dosing. It seems that a strong psychedelic experience is needed to get the best results.”

Efficacy review 
According to the researchers, studies published to date have not examined factors that may moderate psilocybin’s effects, such as type of depression, past use of psychedelics, dosage and publication biases. 

The review, published in The BMJ, includes seven relevant trials, with a total of 436 patients with depression. It includes studies where psychotherapy was present in the experiment and control conditions to ensure the psilocybin effects are distinguished from those of psychotherapy. 

The clinical trials measured depression score changes through the statistical method Hedge’s g, where a score of 0.2 indicates a small effect, 0.5 is moderate and 0.8 or more a significant effect. 

The researchers found a significant benefit of psilocybin treatment, at a 1.64 depression score change in Hedge’s g. 

More research is needed to evaluate psilocybin’s effectiveness under real-world conditions.Real-world applications   
However, the authors caution that high variation levels between trials resulted in a low certainty of evidence to support a robust antidepressant effect of psilocybin. Moreover, the generalizability of the findings was limited due to a lack of participant diversity. 

In clinical trials, patients receive psilocybin in a calm room, supervised by a psychotherapist, which the authors note may be unlikely to achieve in a healthcare system. The clinical trials also did not measure pre-treatment expectations and the extent to which participants knew they were being treated with either psilocybin or a placebo. 

Keedwell highlights: “There are some concerns about expectation effects because the majority of patients knew when they were getting the active condition or the higher dose of the same drug. However, these concerns are tempered by the fact that improvements were maintained for up to 12 weeks in one study.” 

He also notes that doses might need to be adjusted to body weight to achieve a solid psychedelic experience for the best results.

“The main disadvantage is that some patients find the psychedelic effects unpleasant, and care must be taken to ensure a calm environment for the treatment. Psychological preparation and debriefing, before and after dosing, respectively, are crucial.”

It seems that a strong psychedelic experience may be needed to get the best results.Next steps  
A growing body of research supports the potential use of psychedelics such as psilocybin to address depressive symptoms. For example, a clinical trial found a “rapid and robust response” with the compound last year. 

The review’s authors underscore that more information is needed about potential effect modifiers and evaluate psilocybin’s effectiveness under real-world conditions, suggesting that pragmatic clinical trials and real-world data could help fill those gaps. 

According to the review’s conclusions: “The highly standardized treatment setting, high cost and lack of regulatory guidelines and legal safeguards associated with psilocybin treatment need to be dealt with before it can be established in clinical practice.”

Moreover, they note that they cannot differentiate between individuals most likely to benefit from the treatment and those who might experience adverse events. 

Earlier this year, the EU agreed to fund the PsyPal clinical trial, coordinated by the Dutch University Medical Center Groningen, to evaluate the therapeutic potential of psilocybin therapy for palliative care patients. 

Meanwhile, an online survey found that 79% of Canadians support using psilocybin for patients at end-of-life. 

By Jolanda van Hal