From cognitive effort to psychedelics and personalized brain stimulation
I recently received an R01 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to test a new treatment approach for alcohol use disorder: combining psilocybin with personalized brain stimulation. It is the first R01 awarded within the Johns Hopkins Center for Psychedelic and Consciousness Research, which makes it an important milestone for me and for our center.
More broadly, I find it remarkable to see federal funding supporting this edge of psychedelic science. This is a particularly experimental idea: to our knowledge, psychedelic administration and noninvasive brain stimulation have not previously been tested together in a published clinical study. The approach goes a step further by using each participant’s own brain activity to personalize where stimulation is delivered, targeting circuitry involved in the regulation of alcohol craving. Receiving federal support to rigorously test an idea this new feels significant—not only personally, but as an indication of how far the field has moved and the kinds of mechanistic questions it is now possible to ask.
The idea itself began somewhere much more personal.
During my time with a loved one struggling with alcohol use, I noticed that he increasingly had difficulty regulating his drinking. I began observing the pattern closely: certain cues reliably led to craving and then drinking. Finishing work, for example, could become a cue. Even when there was a genuine intention to regulate drinking, that intention often failed to translate into behavior.
I began thinking about regulation as a kind of muscle. When a muscle is strong, exercising it is relatively easy. But when it has become weak from lack of use, exercising it becomes more effortful. The cost of engaging it increases, meaning that even greater motivation is required to do the very thing needed to strengthen it.
This way of thinking immediately connected to my academic past. My PhD research examined the effort costs of cognitive control—how the brain weighs the value of exerting control against the cost of doing so. Alcohol use disorder presented an interesting version of this problem: if regulating craving is itself costly, relying on someone to repeatedly engage that regulatory system in order to strengthen it creates something of a circular problem.
That led me to a different question: What if we could help exercise the regulatory system from the outside?
Our study will recruit 72 people with alcohol use disorder and use fMRI to identify, within each individual, prefrontal circuitry involved in regulating alcohol craving. We will then use personalized intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, to repeatedly engage that circuitry. In this sense, brain stimulation provides a way of exercising the “regulatory muscle” that does not initially depend entirely on a person’s moment-to-moment motivation to recruit it.
The second part of the idea grew directly from my work in psychedelic neuroscience. Psilocybin may produce a period of enhanced neural plasticity—a window during which patterns of brain function may be particularly amenable to change. The R01 therefore uses a 2 × 2 factorial design, combining active or sham personalized iTBS with either 30 mg psilocybin or a 3 mg psilocybin control. This allows us to ask what each intervention does independently, but more importantly, whether targeted stimulation can capitalize on the period of plasticity following psilocybin.
We will use fMRI, TMS-EEG, EEG, and clinical measures of craving and drinking to follow this process across multiple levels—from changes in brain circuitry to changes in behavior. The goal is not simply to ask whether two treatments work better together. It is to test a mechanistic idea: can we identify a regulatory circuit that is struggling to engage, create conditions that make it more plastic, and then deliberately exercise it?
For me, the project brings together what might otherwise look like separate chapters of my scientific career: my early work on cognitive control and effort, my work in psychedelic neuroscience, and my more recent work using brain stimulation to causally probe and modify human brain function. And it turns a question that emerged from watching a very human struggle unfold in front of me into one that we can now test scientifically.