Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach

This theory-building literature review (2021) proposes a model that explains how psychedelics can reduce the negativity bias in depressed patients according to Research Domain Criteria (RDoC), a framework that investigates the underlying neurobiology of clinical symptoms across multiple levels of explanation. It is proposed that psychedelics improve depressive symptoms via a similar mechanism as the antidepressant vortioxetine, by stimulating neuroplasticity in the prefrontal cortex and the hippocampus, and decreasing negativity bias through the restoration of deficits in pattern separation.


“The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.”

Authors: Igor Magaraggia, Zilla Kuiperes & Rudy Schreiber


Sometimes we can get stuck in a thought loop. We humans have the great ability to be excited about something that happens in the future. The anticipation before going to a concert (again) can be just as great as the actual experience at the venue. This works the other way around too. If we expect to feel bad when it rains, if we dread going out that day, we sure will feel bad (without even having left the house). Or when we ascribe anxious nerves as a sign that we can’t perform that next business presentation, the chances increase for you not feeling your best.

All this to say that our patterns in our heads have a strong influence on how we feel, even before the actual events in the real world happen. Or when they happen, they can reinforce our patterns, be they negative or positive. And as you may have guessed from the title of this section, psychedelics are a way to separate thought patterns.

The current paper investigated the therapeutic process of psychedelics through a Research Domain Criteria (RDoC) framework. This takes into account the many levels at which psychedelic-assisted therapy works. It tries to combine everything from genes (which influence we spoke of last week) to the self-reported effects.

This is what the study concluded

  • Psychedelic stimulate the growth of neuronal cells (in the hippocampus) and specifically lead to the growth and strengthening of dendrites (the ‘receiving antennas’ of a cell)
  • This then leads to better resilience in the face of (chronic) stress, both at the level of neurons as subjectively experienced
  • This then leads to an increase in cognitive flexibility, less negative bias, and thus fewer depressed symptoms

Within this framework, with the assistance of psychedelics, a depressed person is now better able to form new memories without the older (negative) memories clouding their judgment. And so breaking free from old thought patterns.

When looking at psychedelic-assisted therapy specifically, one could say that psychedelics make one more receptive to the learning of new patterns and storing new (more positive) memories and self-image. What the most effective dose, form of therapy, and substance will be for which situation is a question that many are now working on.

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