Two new major studies tackle what many researchers believe to be the central unresolved issue in the assessment of psychedelics as treatment for depression: Whether the apparent benefits are inflated by failures of blinding. And the results appear contradictory.

A large meta-analysis of studies conducted under equal unblinding conditions showed that psychedelic-assisted therapy (PAT) may be no more effective than traditional antidepressants when patients know what drugs they are actually taking.

“The efficacy of psychedelic therapy may have been overestimated by not paying attention to blinding-related issues,” lead investigator Balázs Szigeti, PhD, clinical data scientist, Translational Psychedelic Research Program, University of California San Francisco, told Medscape Medical News.

“This does not mean psychedelic therapy is not a valuable treatment option, but it’s probably not as effective as early research indicated,” he added.

The other study — a rigorously designed randomized clinical trial (RCT) that also attempted to address the blinding issue — lends tentative support to the antidepressant effects of psychedelics, in this case psilocybin.

The EPISODE trial missed its primary endpoint of at least a 50% improvement in depressive symptoms with high-dose psilocybin plus psychotherapy but did find a clinically meaningful benefit on some secondary measures.

“Although results suggest potential efficacy, the divergence between primary and secondary outcomes renders the findings inconclusive and calls for cautious interpretation and replication,” the authors wrote.

Both studies were published online on March 18 in JAMA Psychiatry.

Tackling the Unblinding Dilemma

Because psychedelics produce striking subjective effects, participants can often correctly guess their treatment allocation — up to 90%-95% in some studies — raising concerns that expectations inflate outcomes.

Szigeti and colleagues designed their meta-analysis to address thus “functional unblinding,” by comparing PAT with open-label antidepressant therapy, where patients likewise knew what they are receiving.

They pooled data from 24 trials — eight psychedelic studies with 249 patients and 16 open-label antidepressant trials with 7921 patients.

Under these “equal unblinding” conditions, there was no statistically significant difference in patient improvement following psychedelic therapy or open-label antidepressant therapy. The estimated difference on the 17-item Hamilton Depression Rating Scale (HAM-D 17) was 0.3 points, favoring open-label antidepressants (P = .73).

“Not only was the difference not clinically meaningful, but there was practically no difference at all; according to both Bayesian and frequentist estimates, the difference was negligible [and] this result was robust across variations in study selection,” the investigators wrote.

“These results argue against highly optimistic narratives surrounding psychedelic-assisted therapy and highlight the importance of blinding integrity,” they concluded.

They noted that their findings don’t show that PAT doesn’t ease depressive symptoms — just that it does not appear to work better than traditional antidepressants.

EPISODE Optimism?

In the EPISODE trial, Lea Mertens, MSc, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany, and colleagues enrolled 144 patients with treatment-resistant depression.

Using a triple-blind design, they randomized participants into four groups (2:2:1:1) receiving two doses 6 weeks apart as follows: placebo (nicotinamide, 100 mg) followed by 25 mg psilocybin; 5 mg psilocybin followed by 25 mg psilocybin; 25 mg psilocybin, then 5 mg; or two doses of 25 mg psilocybin — all embedded in psychotherapy sessions.

These design features, intended to mitigate unblinding, included nicotinamide and low-dose psilocybin as “active” comparators and ensured all participants would eventually receive a high dose of psilocybin. Even so most participants (86%) correctly guessed when they had received the high dose.

On the primary endpoint of response at 6 weeks, defined as ≥ 50% reduction in HAM-D — the trial was negative. Response rates were not significantly different with 25 mg psilocybin, 5 mg psilocybin, or placebo (17%, 12.5%, and 10.6%, respectively).

However, on key secondary outcomes — response on the Beck Depression Inventory II (BDI-II) and the mean change from baseline on the HAM-D 17 and BDI-II at week 6 — provided “exploratory evidence for clinically meaningful” reductions in depressive symptoms for 25 mg psilocybin vs comparators.

The antidepressant effects of 25 mg psilocybin were particularly pronounced at 1 week, suggesting a rapid antidepressant response, and persisted at 6 weeks.

Safety findings were broadly consistent with earlier studies. Psilocybin 25 mg was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin 25 mg — including one case of hallucinogen persisting perception disorder.

“While overall this constituted an inconclusive trial, these results add to the existing evidence on the potential of psilocybin treatment for depression,” EPISODE investigators wrote.

No Silver Bullet

While more research is needed, Szigeti said it’s likely that neither psychedelics nor antidepressants will top the other for efficacy.

“I think when it’s all said and done, neither treatment will be clearly better than the other. Rather they will have their own pros and cons and some patients will respond better to antidepressants while others to psychedelics, Szigeti said. “I do not think psychedelics will be the silver bullet some have promised, but more than likely they will be a useful addition to the clinician’s toolkit.”

Commenting on the findings for the UK nonprofit Science Media Centre (SMC), several outside experts noted that the data collectively sharpen, rather than resolve, the debate.

B oth studies are of “considerable interest as, in different ways, they address perhaps THE outstanding issue in the assessment of psilocybin and other hallucinogens as therapeutic tools in treatment-resistant depression — blinding,” David Owens, DPhil, professor emeritus of clinical psychiatry, The University of Edinburgh, Edinburgh, Scotland, said in the statement.

“I think both these studies, especially the RCT, keep the project alive, but appropriately temper that unwarranted enthusiasm to which clinicians are so prone!” Owens added.

T aken together, these two studies provide “further support for psilocybin leading to clinically meaningful benefits in patients with treatment-resistant depression,” Hamish McAllister-Williams, MB ChB, PhD, MD, professor of affective disorders, Newcastle University, Newcastle upon Tyne, England, said in the SMC statement.

“However, the treatment is not a panacea with many patients not achieving at least a 50% improvement in symptoms, and there remain concerns about how much of the effect seen may be driven by a placebo response,” McAllister-Williams said.

“Ultimately, the most important question remains — how long do the benefits seen last for? If the effects are sustained over time, then the question of placebo response becomes more of a moot point,” he noted.

James Rucker, MBBS, PhD, of the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, England, offered another perspective on the meta-analysis’ findings that depression scores were no different between PAT and antidepressants when blinding was removed.

“In some ways this is reassuring, as it reconfirms that psychedelic therapy probably does have a true antidepressant effect,” he said in the statement.

“On the other hand, it also suggests that a significant part of this effect is mediated by a positive expectancy effect derived from a participant knowing that they are receiving treatment,” Rucker added.

The EPISODE trial offers “tentative support” for antidepressant efficacy of high doses of psilocybin, albeit relatively temporary in most cases, he noted.

“As more and more clinical trial evidence around psilocybin accumulates, it highlights the limitations of the RCT paradigm in unpicking the undoubted expectancy effects that come with a drug like psilocybin from the more biological effects we are used to from more traditional antidepressants like SSRIs [selective serotonin reuptake inhibitors]. However, since both are important in the treatment of depression, psilocybin therapy represents an increasingly intriguing option,” Rucker added.

The meta-analysis had no funding. Szigeti had no disclosures. One author received consulting fees from Roche. The EPISODE trial was supported by a grant from the Federal Ministry of Education and Research (BMBF). A complete list of author disclosures is available with the original article. McAllister-Williams was a principle investigator in the COMPASS phase 2 trial. Rucker reported leading commercially and publicly funded clinical trials using psychedelics. Owens had no disclosures.