For many patients with serious neuropsychiatric conditions—including post-traumatic stress disorder (PTSD), alcohol use disorder (AUD), and major depression—existing medications are of limited efficacy. NYU Langone Health is at the forefront of research aimed at finding new pharmacologic approaches, including the use of compounds long regarded as illicit drugs.

Exploring the Potential of Psilocybin

Investigators at NYU Langone are probing the efficacy of psilocybin, a hallucinogenic compound derived from mushrooms, for treating a number of disorders. Classified as a Schedule I controlled substance, the drug requires special waivers for study use.

Michael P. Bogenschutz, MD, professor of psychiatry, and Stephen Ross, MD, associate professor of psychiatry and director of the Addictive Disorders and Experimental Therapeutics Research Laboratory, are leading a randomized, double-blind trial in which approximately 100 patients with AUD will be given orally administered psilocybin or placebo under supervised conditions. Participants will participate in 2 medication administration sessions of 8 hours, each with follow-up, as well as a 12-week psychotherapy program which combines evidence-based approaches to AUD with standardized preparation and debriefing. Following completion of the 34-week double-blind period, participants will be offered an additional psilocybin session. To date, 91 patients have been treated.

This phase II trial grows out of a pilot led by Dr. Bogenschutz—the first clinical study ever conducted of psilocybin as a treatment for AUD. In that study, published in 2015 in the Journal of Psychopharmacology, 10 volunteers received the drug under similar circumstances. Abstinence increased significantly after administration and was largely maintained at 36 weeks. “The current trial is the largest that has been done with psilocybin for any condition,” Dr. Bogenschutz notes. “We’re hopeful that it will give us a clear signal as to whether to proceed to phase III for an alcohol use disorder indication for this therapy.”

NYU Langone is also pioneering research into psilocybin as a treatment for patients with cancer-related psychiatric and existential distress. In a landmark 2016 study led by Dr. Ross, 29 subjects with advanced cancer were given a single dose of psilocybin or placebo in 2 consecutive sessions; after the drug session, 80 percent achieved relief from distress (based on clinical evaluation scores for anxiety and depression symptoms) that lasted for more than 6 months. Dr. Ross recently applied for funding of a phase III trial for this indication, which if approved by the U.S. Food and Drug Administration (FDA) could lead to psilocybin being rescheduled and available as a prescription medicine.

Over the past year, the FDA has granted psilocybin treatment a breakthrough therapy designation for two other conditions: treatment-resistant depression and, in November 2019, major depressive disorder. The latter approval was granted to facilitate an ongoing phase II trial coordinated by the nonprofit Usona Institute. NYU Langone is participating in that national study with Dr. Ross as site principal investigator.

“We are a world leader in psilocybin research,” he observes. “Other institutions are studying this medication for one or two disorders, but the range of our work sets us apart.”

Putting Cannabidiol and MDMA to the Test

Research in animal models suggests that another compound derived from a Schedule I substance—cannabidiol (CBD), a nonpsychoactive component of marijuana—might be effective in controlling conditions related to anxiety and addiction. Dr. Bogenschutz is leading a proof-of-concept study funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) investigating the use of CBD for treating alcohol abuse disorder. In this double-blind study, 40 participants will be randomized to receive CBD or placebo daily for 4 weeks and will then switch treatments for another 4 weeks; their alcohol use will be tracked for the duration.

A parallel study of CBD for veterans and civilians with AUD and co-occurring PTSD is being led by Charles R. Marmar, MD, the Lucius N. Littauer Professor of Psychiatry, chair of the Department of Psychiatry, and director of the Steven and Alexandra Cohen Veterans Center for the Study of Post-Traumatic Stress and Traumatic Brain Injury.

In addition, Dr. Ross was recently awarded a grant by the National Institute on Drug Abuse (NIDA) to study CBD in treating chronic pain associated with radiculopathy, a syndrome caused by compression of nerve roots in the spinal column. Patients taking opioids for maintenance therapy will be weaned onto CBD with the aim of preventing opioid addiction and preventing overdoses in this vulnerable patient population.

NYU Langone is also participating in multisite phase III trials, sponsored by the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), of MDMA—a drug popularly known as ecstasy or molly, and chemically similar to hallucinogens and stimulants—for PTSD. This treatment was granted breakthrough therapy status in 2017, after phase II trials with 107 participants showed that 68 percent no longer had PTSD after 2 to 3 sessions of MDMA-assisted psychotherapy. “From what we’ve seen so far, this drug looks very promising,” says Dr. Bogenschutz, the site principal investigator. “If these phase III studies replicate the safety and efficacy found in phase II, MDMA could have an enormous impact in the treatment of PTSD.”

A New Use for an Old Medication

Topiramate was approved by the FDA in 1996 as an anticonvulsant, but several well-designed studies indicate that it can also be an efficacious treatment for AUD; consequently, it is often used off-label for that indication. A few small studies suggest that the drug may also help control symptoms of PTSD, which shares many neurological characteristics with AUD (involving alterations in incentive salience, stress response, and executive control network functioning). Topiramate is thus a promising candidate for treating patients with PTSD and AUD—a common comorbidity for which no single pharmacotherapy or psychotherapy is available. Little research has been done, however, to investigate that possibility.

In October 2019, Dr. Marmar and Dr. Bogenschutz launched an NIAAA-funded study aimed at filling the gap. The project has three parts. The first is a randomized, double-blind, placebo-controlled clinical trial to test the efficacy of topiramate on 150 participants with co-occurring PTSD and AUD over a 12-week period; alcohol- and PTSD-related outcomes will be assessed at multiple time points. The second component, based on laboratory analysis, attempts to identify plasma biomarkers—including genetic factors—that may serve as predictors of therapeutic response and provide insight into underlying physiological processes. In the third aspect of the study, functional neuroimaging (including functional MRI and magnetoencephalography transcranial magnetic stimulation, or MEG TMS) will be employed to track brain activity before and after treatment.

“By examining the relationship between plasma biomarkers, neurological biomarkers, and clinical response, we hope to gain a better understanding of PTSD and AUD, as well as the effects of topiramate,” Dr. Bogenschutz explains. “Our ultimate goal is to develop a precision medicine approach to treating these debilitating—and often linked—disorders.”