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New phase 2 data adds to the growing interest in the psychedelic treatment as a novel drug to treat MDD.
Psilocybin treatment was linked to significant and sustained reductions in depressive symptoms and functional disability in patients with major depressive disorder (MDD), according to results from a new phase 2 trial.1
A team of US investigators reported data Thursday morning showing psychedelic psilocybin significantly improved critical measures of MDD—including Montgomery-Asberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS) scores—as well as a greater likelihood of sustained response than patients receiving placebo niacin. The novel drug was not without clinical concern, however; investigators additionally observed a greater rate of overall and severe adverse events (AEs) and no increased rate of remission among psilocybin-treated patients.
Led by Charles L. Raison, MD, of the Usona Institute in Fitchburg, WI, investigators sought to analyze single-dose psilocybin’s antidepressant effects—in terms of magnitude, timing and durability—in adult patients with MDD. As has been previously discussed on HCPLive,2 the interest in the psychedelic drug as a potential psychiatric therapeutic has “skyrocketed in recent years,” Raison and colleagues wrote. The field of regulated MDD pharmacology is currently limited in variability and clinical benefit, they wrote, while recent research suggests psilocybin provides a “rapid antidepressant response that far outlasts the presence of the drug in the body.
“However, recent critiques highlight notable limitations in many of these studies, including small sample sizes, assessments by raters likely to be functionally unblinded, an open or waitlist comparator design, and an inadequate assessment of AEs,” investigators wrote. “Larger recent studies have addressed these issues to various degrees, but report primary end points of short duration, leaving open the question of the long-term clinical utility of psilocybin for an often chronic condition such as MDD.”
The team conducted its randomized, controlled trial across 11 US research sites from December 2019 – June 2022. Eligible patients aged 21 – 65 years old with DSM-5 diagnosis of MDD for ≥60 years, as well as moderate to greater symptom severity, were split 1:1 to either single-dose 25 mg psilocybin capsules or 100 mg niacin placebo administered with psychological support.
Patients with a history of psychosis or mania, active substance use disorder (SUD), and active suicidal ideation with intent were excluded from the trial. Additionally, patients taking psychotropic agents who otherwise met inclusion criteria were eligible after a medication taper.
Raison and colleagues sought a primary outcome of change in central rater-assessed MADRS score—a 0 – 60-point scale in which greater scores indicate more severe depression—from baseline to day 43. Secondary outcomes included change in MADRS score from baseline to day 8, change in SDS score from baseline to day 43, and sustained treatment response and remission per MADRS.
The outcomes, along with AEs, were assessed at baseline then 2, 8, 15, 29, and 43 days post-treatment.
The final patient cohort included 104 participants; mean age was 41.1 years old, and 52 (50%) were women. Thirteen patients reported treatment-resistant depression (TRD), and 23 underwent a medication taper prior to randomization. Half (n = 52) of patients had reported ≥3 prior depressive episodes at baseline. Investigators administered psilocybin to 51 participants, and niacin to 53 participants.
For the primary outcome, psilocybin was associated with a statistically significantly improved mean MADRS score among treated patients (-19.1; 95% CI, -22.7 to -15.5) versus niacin (-6.8; 95% CI, -10.5 to -3.1) at day 43 (mean difference, -12.3; 95% CI, -17.5 to -7.2; P <.001).
Patient response to psilocybin per MADRS was indeed fast-acting; in the key secondary outcome, the psychedelic arm achieved a mean -17.8 change in score at day 8 (95% CI, -21.1 to -14.6) versus just -5.8 (95% CI, -9.1 to -2.6) among the niacin arm.
Investigators additionally observed a significantly improved SDS score among psilocybin-treated patients at day 43 versus niacin (mean difference, -2.31; 95% CI, -3.50 to -1.11; P <.001). They additionally reported that 20 (41.7%) patients receiving psilocybin achieved sustained depressive symptom response, versus 5 (11.4%) of patients on niacin (P = .002). However, just 12 (25.0%) patients receiving the psychedelic achieved remission, versus 4 (9.1%) patients receiving niacin (P = .05), an insignificant difference.
Regarding safety, 44 (88%) patients receiving psilocybin reported ≥1 AE through day 43, versus 33 (61%) patients receiving niacin. Through rates of mild to moderate AEs were consistent across the 2 treatment arms, 4 patients receiving psilocybin reported a severe treatment-related AE by day 9—including migraine, headache, illusion, panic attack and paranoia—versus no patients in the niacin arm. Another 22 patients receiving psilocybin reported visual perception effects on the day of dosing, though all cases were resolved by study end.
“The 8% rate of severe adverse events in participants receiving psilocybin was similar to the 10% rate reported in the study by Goodwin et al in participants with TRD treated with a single 25-mg dose of psilocybin,” investigators wrote. “However, in contradistinction to the study by Goodwin et al, no clinically confirmed active suicidal ideation or suicidal behavior occurred in either randomized group.”
The team additionally noted psychedelics may produce AEs “not captured by standard rating scales or may induce unrecognized new psychiatric conditions even as they improve target syndromes.”
In an editorial accompanying the new data, New York institution-based psychiatrists Rachel Yehuda, PhD, and Amy Lehrer, PhD, stressed the emerging fact that, while psychedelic therapies are now associated with robust, rapid, direct and sustained treatment of psychiatric conditions, they are not representative of a “panacea for every patient.”3
“There are no silver bullets in psychiatry,” Yehuda and Lehrer wrote. “In the study by Raison et al, similar to all other reports, there are a significant number of patients who did not respond to therapy. It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms.”
Indeed, Raison and colleagues concluded the single-dose 25 mg psilocybin capsule was associated with clinically and statistically significant reductions in major depression symptoms and functional disability—with caveats for increased likelihood of treatment-emergent AEs and continued research into the likelihood of sustained response and remission.
“These findings add to evidence that psilocybin—when administered with psychological support—may hold promise as a novel intervention for MDD,” they wrote.