Psychedelics: New Research, Regulations, and Horizons

Ahead of his session "Psychedelics Preconference: Psychedelic Horizons" at Psych Congress 2024 in Boston, Massachusetts, Andrew Penn, PMHNP-BC, a clinical professor at the University of California, San Francisco, in the school of nursing, and a Psych Congress Steering Committee member, answered some questions on where psychedelic-assisted therapy is going. Penn examines some of the sources of uncertainty surrounding this conversation, promising areas of research and development, and the current legal and regulatory frameworks in psychedelics. 

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Answers have been lightly edited for clarity. 

Evi Arthur, Associate Digital Editor, Psych Congress Network: What are the primary sources of uncertainty surrounding the therapeutic use of psychedelics, and how do these uncertainties impact research and clinical practice?
 
Andrew Penn, PMHNP-BC: Despite the FDA declining the new drug application (NDA) for midomafetamine (MDMA) assisted therapy for PTSD this summer, I think there are many reasons to be optimistic about the potential uses of psychedelics in psychiatry, particularly as treatments for mood disorders, anxiety disorders, and substance use disorders. In addition to ketamine and esketamine which are psychedelic-like drugs used off label, and with an indication for depression, respectively, there are several phase 3 studies in progress or starting soon examining psilocybin in depression and LSD in generalized anxiety disorder (GAD). 
 
The FDA hearings shone light on some challenges with doing this work, namely around managing expectancy effects on both the part of the study subjects and the researchers. Probably not a surprise to anyone, but it’s difficult to fully mask the difference between placebo and a psychedelic. Psychedelics are not unique in this way—many drugs tend to be easy to distinguish from placebo, but it tends to be fairly obvious to both the subject and the researchers if the subject was given a psychedelic or an placebo. This is known as functional unblinding and can lead to biasing both the subject and researcher. Given the significant enthusiasm, or as some might call it, hype around psychedelics, this led to the FDA questioning the validity of the data that war reported in the NDA.
 
Additionally, there is a challenge with coding what are known as “adverse effects.” If a patient who has been depressed for years begins to smile and laugh, that’s certainly a change from baseline, but is it “adverse”? The FDA was concerned that such an experience might be considered rewarding and that since smiling and laughter are not usually thought of as being “adverse,” that these effects might have been underreported by researchers witnessing them in research subjects. This might be mitigated by simply reporting “changes from baseline;” if a subject comes in without a headache and with depressed affect and now has a headache but is smiling following dosing, those would both be changes from baseline. 
 
PCN: Can you discuss the challenges associated with studying the effects of psychedelics in controlled research settings, and how these challenges might be addressed?
 
Penn: One of the ongoing challenges in PAT research is that this treatment method combines the benefits of psychotherapy, which is then accelerated and supported by a drug. The problem is that psychotherapy is not regulated by the FDA, and the ignorance of the panelists around psychotherapy was quite evident in the advisory hearing that was held by the FDA. Usually, drugs are approved as standalone treatments, which is not how psychedelic treatments have been tested in clinical trials to date. Figuring out how to both keep study subjects psychologically safe and supported as they undergo these treatments while being able to separate out the drug effects from the effects of psychotherapy continues to be a challenge.
 
PCN: What are some of the most promising areas of research and development in the field of psychedelic therapies, and what breakthroughs might we expect in the coming years?

Penn: I think MDMA will eventually succeed in being approved for PTSD. However, it will probably need to be paired with a more evidence-based, conventional psychotherapy or maybe even without psychotherapy to be comprehensible to the FDA. I think psilocybin and other tryptamine and ergotamines such as DMT and LSD respectively are showing great promise in clinical trials for both mood disorders, anxiety, and substance use disorders. Further up the pipe are a number of exciting early stage studies, such as the ones we’ve been doing in our lab at UCSF—looking at psilocybin-assisted therapy as a treatment for eating disorders, bipolar 2, chronic pain, and depression in people with Parkinson disease. While it’s too early to tell if psilocybin will move the needle on these vexing problems, it’s certainly worth watching.
 
PCN: What are the current legal and regulatory frameworks surrounding the use of psychedelics in the United States and how are these frameworks evolving?

Penn: Many cities and even whole states are moving forward with their own laws around psychedelics. Denver was the first to decriminalize personal use of psilocybin. Recently, Oregon voters approved an initiative that allows for adults to have a personal psilocybin experience in a supervised setting. Colorado is operationalizing their Natural Medicines Act, which will allow clinicians to treat patients with psilocybin, along with other liberalizations of state laws around psychedelic use. Massachusetts is voting on a similar proposal this fall. 
 
I think these efforts speak to a certain impatience from the public with the slow pace of the FDA approval process and also speak to the growing disinterest that American society has with continuing a failed policy of widespread drug prohibition, which has served to incarcerate and marginalize many people who use drugs. Similar to the change we’ve seen around attitudes and laws around cannabis over the last 30 years, this shift appears to also be happening around psychedelics. However, increasing access to potent psychoactive substances does pose certain risks to those who are vulnerable to adverse events and we need to pair this liberalization of our drug laws with strong, candid, and honest public health messaging around drug use and how to both reduce risks and maximize benefits associated with personal drug use, much as we have successfully improved messaging around alcohol and tobacco use over the last 30-40 years. If people have better information and they see the source of that information as credible, they make better choices. 
 
PCN: How can we balance the need for regulation with the desire to promote innovation and access to potentially beneficial therapies?
 
Penn: Another challenge of the Controlled Substance Act, the federal regulation that created the schedule I-V system with which most clinicians are familiar, is that it is not scientific but, rather, political. Many substances that might have clinical benefits are placed on schedule I, which makes them even harder to study. Relaxing the ability to study drugs under schedule I could lead to an increased understanding of the potential clinical uses of these drugs, and innovation in the pharmaceutical development space could lead to changes in these molecules that further enhance their benefits while reducing attendant risks. 
 
Meanwhile, patients aren’t waiting for the slow process of the FDA to go through its motions. Many of my patients tell me about going to underground therapists, microdosing psychedelics on their own, or taking psychedelics for personal growth. Most clinicians are woefully unaware of how these substances work, what risks they pose to people with existing mental illness, and how they interact with other medications. Like cannabis 20 years ago, the patients are ahead of the health care profession, and it’s on us to catch up so that we can be the most informed resources to our patients. 

PCN: Is there anything else you would like to share with the Psych Congress Network audience?
 
Penn: Winston Churchill once said “Never let a good crisis go to waste,” and while I wouldn’t call the FDA deciding not to approve MDMA a crisis, the shortcomings of our existing treatments in the face of a tidal wave of mental illness is. This is an opportunity for the psychedelic field to think about how to improve studies so that these treatments can get to patients and for both regulators and drug developers. Every day in our clinics and hospitals, we see the human cost of under-treated mental illness and struggle with the limitations of our existing treatments. Psychedelic therapies must continue to be researched so that perhaps, someday with their help, we will be able to help our patients live their best lives.

Andrew Penn, MS, PMHNP, is a clinical Professor in the University of California, San Francisco, School of Nursing where his teaching has received the UCSF Academic Senate Distinction in Teaching Award, among other recognitions. He has practiced as a psychiatric/mental health nurse practitioner, treating veterans and training residents at the San Francisco Veterans Administration Hospital. As a researcher, he collaborates on psychedelics studies of psilocybin and MDMA in the Translational Psychedelics Research (TrPR) lab at UCSF, serving as Co-PI on a phase 2 study of psilocybin for depression and is currently working on a study using psilocybin to treat depression in patients with Parkinson’s disease. A leading voice in nursing, he is a co-founder of the Organization of Psychedelic and Entheogenic Nurses (OPENurses.org), advocating for the perspective of nurses in psychedelic therapy, he has published on psychedelics in the American Journal of Nursing, Frontiers in Psychiatry, and The Journal of Humanistic Psychotherapy.