The National Institutes of Health (NIH), the world’s largest funder of medical research, has been taking a keen interest in psychedelics over the last few years.
The NIH invests about $41.7 billion annually in medical research mostly in the U.S., with Texas getting the most ($6.7 billion). More than 80 percent of NIH’s funding is awarded for extramural research, largely through almost 50,000 competitive grants to more than 300,000 researchers at more than 2,500 universities, medical schools, and other research institutions in every state.
There are currently 57 NIH-funded projects about psychedelics (6 on psilocybin alone begun in the last three years), totaling $34.4 million, which includes 36 basic and applied research projects for the National Institute of Mental Health (NIMH) funded by $15.4 million.
The NIH has worked closely with the FDA, DEA, and the White House Office of National Drug Control Policy on a proposed framework to facilitate the process of obtaining a DEA registration to conduct research with controlled substances, including psychedelics.
But even as the NIH creates more pathways to psychedelics research—such as the $3 million in funding to researchers at Johns Hopkins Medicine for the first federal grant in 50 years to explore the potential impacts of a psychedelic (psilocybin) on tobacco addiction—the organization still appears to be holding off digging deeper into psychedelics research until the industry addresses what the NIH says are shortcomings in psychedelics research.
In a June 15 letter responding to an inquiry by Congressmen Brian Schatz (D-HI) and Cory Booker (D-NJ) in May about what the NIH is doing regarding psychedelics, Dr. Joshua Gordon, the director of the NIMH, and Dr. Nora Volkow, director of the National Institute on Drug Abuse (NIDA), pointed out that there is a “knowledge gap” problem with psychedelics research, in part due to the lack of participant diversity in clinical trials to date. This includes both racial and ethnic diversity.
They said that they noticed a lack of participants with diverse medical histories, as most psychedelics trials exclude potential participants with a family or personal history of psychosis or suicidal thoughts or behaviors. NIH researchers have also questioned the conduct of participants and therapists during psychedelics sessions.
The NIMH has been supporting research on psychedelics for some time, according to Dr. Gordon speaking at the NIH Workshop on Psychedelics as Therapeutics in January, conducted by the NIMH, the principal federal agency responsible for research on mental illness; the National Institute on Drug Abuse (NIDA), which has already partnered with psychedelic companies; and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
The NIMH collaborated on the first psychedelic to result in any kind of FDA approval for medication derived from ketamine (Spravato). “We’ve been supporting research on ketamine, both at the NIMH in the full research program and on other sites for a couple of decades,” Gordon said during the workshop. “And in fact, it does seem like ketamine can mean effective therapy, rapidly acting therapy for treatment-resistant depression. And it’s not only ketamine, but of course, esketamine, which was developed by a drug company, tested and shown to be effective in treatment-resistant depression through a randomized clinical trial. It is now FDA approved.”
One pathway for NIH funding is in understanding the neurobiological effects of psychedelic medications, including ketamine, but also other psychedelics, Gordon said, citing a paper published in “Neuron” showing that psilocybin has rapid and persistent effects on the growth of dendritic spines in the prefrontal cortex in vivo in mice. “So we can think of NIMH’s interests in studying psychedelics, both in terms of proving that they work and also in terms of demonstrating the mechanisms by which they work. And in fact, the mechanism focus is really part and parcel of the drug development priorities throughout NIMH, when we think of how we want to try to study novel therapies,” Gordon said.
He outlined various pathways for companies to get NIMH funding. “But we have to acknowledge that the NIMH has not played a significant role at this point in the study of the more recent developments with psilocybin and MDMA and other drugs, as they are being taken up by nonprofits and other companies to try to demonstrate their efficacy in disorders such as PTSD and depression.”
Also during the NIH workshop, Dr. Paul Appelbaum, psychiatrist and the director of the Division of Law, Ethics and Psychiatry at Columbia University, discussed the importance of designing research to anticipate the actual clinical use of psychedelics. “So assuming studies continue to suggest therapeutic efficacy for a number of disorders for various psychedelic and related medications, they will become at some point available for clinical use,” he said. “And I would suggest that it’s important for the people who are designing studies to anticipate the issues that will, without doubt, arise as part of that use and design studies that can address those issues. This is often ignored in pre-marketing studies, but I want to suggest that it shouldn’t be ignored here.”
Randomized double-blind tests are problematic in psychedelics, according to Suresh Muthukumaraswamy, a neuropsychopharmacologist from the University of Auckland in New Zealand, also presenting at the NIH workshop.
He said that the purpose of clinical trials is to establish the safety and efficacy of their interventions. “The way researchers establish efficacy is by trying to demonstrate a causal effect between the treatment and outcome,” he said. “The issue we face in psychedelics is that we have very large perceptual experiences that participants are going to experience. So it becomes pretty obvious to the participant about which intervention they might have received,” he said. “So herein lies the crux of the problem. Given the obvious psychoactive effects of psychedelic drugs, those in the active intervention group will likely know that they’ve received the treatment, and therefore they might show a greater treatment response due to expectancy effects. On the other hand, those participants that receive a placebo intervention may know that they have received the placebo intervention and their disappointment may actually decrease in what they would normally have as a placebo response. So we have two push-pull mechanisms, where you might have enhanced the effects of the usual expectancy when participants know that they’ve received the treatment, and a decreased placebo response when they know they’ve received the placebo intervention.”
Dr. Volkow, in her wrap-up of the workshop, said that, at this time, she feels a level of being overwhelmed in terms of a lot of the things for which there are no answers. “But at the same time, I see this as an incredible opportunity to modify the way that we are doing things,” she said. “What is it that the NIH can do to help accelerate research in this field so that we can truly understand what are the potentials and, ultimately, the application of interventions that are based on psychedelic drugs?” she said. “From the perspective of what is it that NIH can do to accelerate research, there are no two ways around it: We need to have a greater in-depth understanding of the characteristics of the drugs that we call psychedelics. I do recognize the concern that we just don’t limit the description of these psychedelic drugs to their pharmacological target. We need to go beyond that and understand the downstream effects the functional consequences,” she said. “As we work forward with the development and testing of psychedelic drugs, we need to bring the patients into the discussions so that the priorities and their concerns are actually incorporated into our research plans. I think we need to basically very clearly understand where we are in history, and what we’ve learned from the past, so that we do not commit the same mistakes and errors.”