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In January, we reported on an investigational psychedelic that alleviated symptoms of depression in a mid-stage trial. In this report, we follow up on what has happened since that study was published.

In the phase IIa trial, an investigational N,N-dimethyltryptamine treatment -- commonly known as the hallucinogen DMT -- significantly reduced depressive symptoms by 7.4 points more than placebo (P=0.02) at 2 weeks after treatment when using the Montgomery-Asberg Depression Rating Scale (MADRS).

The antidepressant effects were seen within just a week after a 21.5-mg infusion of the agent, dubbed SPL026, was administered with supportive therapy.

Since this trial, several other psychedelics have made their way down the developmental pipeline, showing a wide range of psychiatric therapeutic effects.

The Magic of Magic Mushrooms

In August, another phase II trial showed that just a single dose of psilocybin significantly improved depression symptoms and functional disability in patients with major depressive disorder. Here, a 25-mg dose of synthetic psilocybin -- found in Psilocybe mushrooms, commonly known as "magic mushrooms" -- resulted in a sustained 12.3-point (95% CI -17.5 to -7.2) greater improvement versus active niacin placebo in MADRS score on day 43.

With this treatment, which was co-administered with psychological support, patients had a significant improvement in symptoms as early as the second day.

Of note, psilocybin didn't just work well for major depressive disorder. In July, the same single synthetic dose of the psychedelic was found to be safe and tolerable in a phase I study of women with anorexia. Only 10 women were enrolled in the early-stage trial, which reported significant improvements in psychopathology, but no changes in body mass index.

Later in the year, psilocybin eased symptoms of treatment-resistant bipolar depression in a trial of 15 people. MADRS scores decreased by 24 points at 3 weeks in participants with bipolar type II disorder, and 11 patients even met remission criteria.

"Psychedelics have the potential to ease the suffering of many patients with difficult-to-treat mood disorders, and some folks with a cyclical mood disorder could benefit," study author Scott T. Aaronson, MD, of the Sheppard Pratt Health System in Baltimore, told MedPage Today in early December.

Other trials this year also highlighted psilocybin's therapeutic effects on treatment-resistant depression -- with or without the aid of traditional antidepressants -- and depression for patients with cancer.

MDMA, Ketamine Gain More Traction

In September, positive findings from a late-stage trial highlighted MDMA's therapeutic effects on post-traumatic stress disorder (PTSD) symptoms. Building on phase II findings released in 2021, adding MDMA pharmacotherapy to psychotherapy significantly improved PTSD symptoms compared with placebo with psychotherapy (least squares mean change -23.7 vs -14.8). The compound, which was granted a breakthrough therapy designation in 2017, also significantly improved clinician-rated functional impairment in a diverse patient population.

"The hope is that MDMA and psychedelics in general might have a signal in not just PTSD and depression ... but in other mental health disorders as well," study author Jennifer M. Mitchell, PhD, of the University of California San Francisco, told MedPage Today in the fall. "The objective will be to evaluate all of the psychedelics in each of these different disorders to determine how far the therapeutic efficacy reaches."

Because of the successes observed in phase II and III trials, MAPS Public Benefit Corporation announced in mid-December that it submitted asking for priority review. If approved, the Drug Enforcement Administration would be required to reschedule MDMA, making it available for prescription medical use, the developer said.

While not a classic psychedelic in the traditional sense, ketamine also continued to prove its therapeutic benefits throughout 2023. According to a major study published in May, ketamine worked just as well as electroconvulsive therapy -- the "gold standard" for treatment-resistant depression. Following a 3-week treatment period, 55.4% of the patients in the ketamine group and 41.2% of those in the electroconvulsive therapy group had a treatment response, a 14.2% difference (95% CI 3.9-24.2).

In IV form, ketamine is only FDA approved as a sedative, analgesic, and general anesthetic. Esketamine (Spravato) nasal spray is approved alongside an oral antidepressant for treatment-resistant depression.

"Ketamine's effectiveness, in the aggregate results, looks a bit better than electroconvulsive therapy for major depression not associated with psychotic features," lead investigator Amit Anand, MD, director of Psychiatry Translational Clinical Trials at Mass General Brigham in Boston, told us at the American Psychiatric Association annual meeting.

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