Psychedelics Said to Relax Patients’ Internal Confidence to Promote Plasticity

One of the key questions in psychedelic medicine is quantifying how this class of drugs operates at the higher-order brain level. It is known that they activate serotonin 2A receptors, which eventually leads to states like increased empathy and out-of-body experiences. What happens in between?

As part of a wide-ranging talk on psychedelic neurobiology, Robin Carhart-Harris, Ph.D., the Ralph Metzner Distinguished Professor of Neurology and Psychiatry at the University of California, San Francisco (UCSF), postulated that psychedelics work by lowering a person’s confidence—but in a good way.

As Carhart-Harris, who is also the director of the Psychedelics Division at Neuroscape (UCSF’s new translational neuroscience center) explained, the brain operates as an inference machine. “It makes a model of the world it inhabits and then gradually adapts that model over time,” he said. “But the built-in model takes precedence over external data.”

Common examples of this model are optical illusions that trick the brain into seeing movements that don’t exist. But after viewing a misleading image over and over again, the illusion fades.

However, when some people are presented with new information that contradicts already held beliefs, the new information does not penetrate. Carhart-Harris suggested this phenomenon, known as “canalization,” is a fundamental aspect of behavioral disorders. Canalization refers to the entrenchment of people’s models such that they resist new inputs. Indeed, most psychiatric illnesses have a component of cognitive or behavioral inflexibility: the self-defeating thoughts associated with depression, the cued fear responses associated with anxiety disorders, the repetitive behaviors of obsessive-compulsive disorders, to name a few. This may explain why psychedelic compounds have shown promise in the treatment of a wide range of disorders in preliminary studies.

Based on numerous studies analyzing neuroimaging and EEG data from people under the influence of psychedelics, Carhart-Harris believes these drugs modulate the brain’s precision weighting.

“Precision weighting is a measure of confidence assigned by the brain,” Carhart-Harris explained. The brain then infers the current world in a top-down manner, starting with the elements assigned with absolute certainty and moving on to elements with lower confidence.

Psychedelics relax that confidence such that the brain is forced to rely more on current stimuli and less on built-in beliefs, effectively inferring its current environment from the bottom up rather than top down. Carhart-Harris said it is akin to having your eyes closed for a while and then opening them when you are in a strange place.

That moment of relaxation creates a period of tremendous plasticity in which new neural connections are ready to be made, effectively teeing up the brain for change. Some of Carhart-Harris’ studies have found that negative affect, especially negative beliefs about oneself, are particularly malleable during this mental state, which highlights why psychedelic-assisted psychotherapy can promote rapid improvements in mood or other behaviors. ■