The potential benefits of psychedelic drugs have led to multiple major clinical trials in the quest to become FDA-approved medications. In one such recent trial, David J. Hellerstein, MD, a psychiatrist in the Division of Clinical Therapeutics, Department of Psychiatry at NewYork-Presbyterian/Columbia University Irving Medical Center, served as a principal investigator in a phase 2b clinical study of psilocybin – a psychedelic compound in magic mushrooms. Dr. Hellerstein is also Director of the Depression Evaluation Service at the New York State Psychiatric Institute and Professor of Clinical Psychiatry at Columbia.
Dr. David Hellerstein
Dr. Hellerstein and researchers at multiple sites found that a single dose combined with psychological support generated a rapid response and significant reduction in depressive symptoms. “We now have evidence from a large, well designed trial that psilocybin may be effective for people with treatment-resistant major depressive disorder, a common and devastating condition,” says Dr. Hellerstein. “This is the first psychedelic study to rigorously evaluate rates of adverse events and serious adverse events, which are of utmost concern when using this powerful class of drugs among patients with severe disorders. Our understanding of these risks is essential to move toward FDA approval and can allow clinicians to develop strategies to manage risks in order to optimize outcomes.”
The study focused on COMP360 psilocybin therapy developed by a London-based biotech company that partnered with 25 sites around the world, including Columbia and the New York State Psychiatric Institute. The investigators randomized 233 patients to receive a single dose of one of three doses of COMP360 – 25 mg, 10 mg, and 1mg, a dose that was essentially a placebo – in conjunction with support from therapists trained to guide people through psychedelic-assisted treatments. Patients were followed up for 12 weeks. The 25 mg and 1 mg dose cohorts comprised 79 patients each and the 10 mg dose cohort had 75 patients. All participants were taken off antidepressants before the study.
“It’s rare to see such positive outcomes of clinical trials in this disease area, which is why the results of the COMP360 trial are so significant. I hope this represents a major step in finding new options for people living with treatment-resistant depression.” – Dr. David Hellerstein
The study found that participants administered the highest dose of psilocybin had the steepest decline in depressive symptoms. Patients reported a rapid remission at three weeks that was sustained at the three-month mark. In addition to showing the efficacy of the higher dose, the study showed that the lower dose (10 mg) was not effective. Key results included:
Depression Symptoms Patients who received a 25 mg dose with psychological support experienced a highly statistically significant reduction in symptoms of depression after three weeks. The difference between the 25 mg group and 1 mg group was -6.6 on the Montgomery-Åsberg depression rating scale at week 3.
Durability Double the patients who received 25 mg (20.3 percent) had a sustained response at week 12, compared to those who received 1 mg (10.1 percent).
Tolerability COMP360 psilocybin was generally well-tolerated. On the day of administration, headache, nausea, and dizziness were the only adverse events where a dose-related increase in incidence was evident. There were no clinically significant differences between the dose group in vital signs or clinical laboratory tests observed during the study.
Adverse Events Suicidal ideation and intentional self-injury were seen in all treatment groups (as is regularly observed in a treatment-resistant depression population), and the majority occurred more than a week after the psilocybin session. There was no mean worsening of suicidal ideation scores in any treatment group. Suicidal behaviors were reported at least one month after COMP360 administration for three non-responders in the 25 mg arm.
The study was presented at the May 23, 2022 annual meeting of the American Psychiatric Association.
“This is an important study because we need more treatments for depression,” says Dr. Hellerstein. “Now we can move on to an even larger study to determine the best treatment approach. If we can identify a therapy that offers a benefit with just one treatment, we may be able to make a significant dent in the burden of treatment-resistant depression.” Planning is now underway for four phase 3 studies of COMP360. The Depression Evaluation Service at the New York State Psychiatric Institute/Columbia Psychiatry will be a participating site for three of these trials.
Three Decades of Classical Psychedelic Studies
Dr. Hellerstein and David Bender, MD, conducted a clinical review of classical psychedelics, which was published in the June 2022 issue of Psychopharmacology. Dr. Bender, a 2021 graduate of Columbia University Vagelos College of Physicians and Surgeons, co-wrote the clinical review paper with Dr. Hellerstein. Their goal was to draw on published data to assess potential risks and benefits of psychedelic drugs as therapeutics, as well as to synthesize current understanding to generate successful future research.
Their review included studies conducted since 1991 and identified 14 clinical trials of classical psychedelics, including 11 of psilocybin, one of lysergic acid diethylamide, and two of ayahuasca. They determined that these studies largely support the hypothesis that small numbers of treatments with psychedelic-assisted psychotherapy can offer significant and sustained improvement to symptoms of multiple psychiatric conditions. The researchers also noted that no serious adverse events attributed to psychedelic therapy were reported.
Dr. Hellerstein and Dr. Bender concluded that the substantial data gathered in the past 30 years suggest that psychedelics are a potent treatment for a variety of common psychiatric conditions, though the means of employing these substances to minimize adverse events and maximize therapeutic effects remains controversial.
“Treatment-resistant depression is one of the biggest challenges we face in psychiatry, and chances of success decrease with each treatment that a patient tries,” adds Dr. Hellerstein. “It’s rare to see such positive outcomes of clinical trials in this disease area, which is why the results of the COMP360 trial are so significant. I hope this represents a major step in finding new options for people living with treatment-resistant depression.”