The Mechanism of Psychedelic Therapy, Explained

Psychedelics such as ketamine, psilocybin, MDMA, LSD, mescaline, and ibogaine produce alterations to sensory, self, time, and space perception “so alien to everyday experience that they shed new light on the workings of these everyday mental functions.”[i]

Multiple well-designed research studies have shown the remarkable promise of psychedelic therapy for depression, PTSD, and addiction. Now an article published June 14 by Nardou, Sawyer, and Song et al presents the first comprehensive mechanism explaining how various psychedelics, each interacting with different combinations of neurotransmitter systems, have common therapeutic effects.[ii]

The core of this article revolves around the fact that the developing brain has critical time periods during which specific functions are learned—for example, bonding in geese, songs in finches, and language in humans. During specific periods of brain development, the nervous system exhibits heightened sensitivity to stimuli related to specific functions, as well as increased malleability for synaptic circuit modifications. The constrained window of time during which the brain can develop a specific function is called a critical period. Recently, a novel critical period for social reward learning was discovered. Can psychedelics possibly reopen this critical period, allowing a second period during adulthood for social reward learning?

Mice have a critical period when classical conditioning can use social contact as the rewarding stimulus. After this period, social contact is no longer sufficient reward to propel classical conditioning. However, pretreatment with a variety of psychedelics, including ketamine, psilocybin, MDMA, LSD, and ibogaine, are all followed by a reopening of social reward learning in adults long after the critical period had been closed.

A time-honored research protocol called conditioned place preference (CPP) was used to measure whether social contact provides sufficient reward to develop a preference for the place where the social contact occurred. After adult mice were pretreated with any of the above psychedelics, social contact was once again sufficiently rewarding to create place preference, and this was long after closure of the normal critical period when social contact had last been rewarding enough to create place preference.

And here is the remarkable thing: This research demonstrated not only that reopening the social reward learning critical period in mice is a shared property across psychedelic drugs. It also found that “the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans.” Each psychedelic keeps the window for social reward learning open in direct proportion to how long its acute effects last in humans. Ketamine’s acute dissociative impact on humans lasts the shortest time of these tested psychedelics, and it kept the window of social reward learning in mice open for the shortest time. Ibogaine, the acute effects of which can last days, reopens social reward learning the longest. In all cases, the window of social reward learning remains open far longer than the acute impact of any psychedelic.

The fact that such different psychedelics had the same ability to reopen a period of social reward learning, which is the linchpin for their therapeutic effect, suggests a deeper underlying mechanism, and Nardou et al supply an apparent mechanism. They analyzed messenger RNA in the reward center (nucleus accumbens) before and after administering psychedelics and found evidence for the expression of a significantly different set of genes induced by the psychedelics. These genes appear related to aspects of the extracellular matrix surrounding nerve cells, resulting in altering the impact of oxytocin, the pro-social “hug” hormone, on dendrites in a way that heightens dendritic sensitivity to social contact. The critical period of social reward learning is reopened in adulthood. This provides the ability to respond to social contact in ways that restructure the nervous system. Under the proper set of therapeutic influences, the neural infrastructure of depression, PTSD, and addiction can be restructured toward health.

The process of restoring oxytocin-mediated impact on the nucleus accumbens is called “metaplasticity.” Metaplasticity means dendrites’ response to stimuli is altered to reopen the critical period of social reward learning. An analogy might be the difference between eating cake batter before baking it versus having the electricity turned on for a period to be able to bake the ingredients before eating. The same ingredients, but differently processed. Opening the critical period of social reward learning is akin to having the oven on long enough to bake the ingredients. Cake versus batter.

"Psychedelics reopen the social reward learning critical period" is a rich, but complicated, article that describes complex research. While it is hard to wrap your arms around the entire study, it is easy to understand the bottom line: The theory and mechanism of psychedelic therapy have been elevated to new levels of legitimacy and verifiability.