A previous post began to explore the question of whether 2,5-dimethoxy-4-iodoamphetamine (familiarly known as DOI) might be the Holy Grail, the coveted magic bullet, the ne plus ultra of addiction cures. A paper published earlier this year by Nature.com dives right in by describing in great detail the experimental work that has been done with lab mice because:

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored.

One of the main questions is, does this stuff work only when the subject is actively and actually tripping, or does it still affect structural brain plasticity and cognitive flexibility after the acute drug experience has worn off? In mice anyway, the adaptation to, for instance, a “novel reversal in task structure is still in effect a week later. Other interesting features came to light, like this one:

DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues…

Researchers also discovered the importance of “time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.”

All in all, the consensus is that such serotonergic psychoactive substances induce acute changes in self-perception, as well as in the perceptions of time and the immediate environment, all adding up to an extraordinary state of consciousness. Furthermore, they promote improvements in psychological well-being that are confidently identified as long-term. Consequently,

DOI’s facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviors and a resistance to change seen in depression, anxiety, or addiction.

And whoa! There it is, the A-word. So, the mind can be molded like clay, and DOI is a substance that can do it. So, why are we not using this astonishing fact to battle addiction already? One reason is, although hints and promising leads are plentiful, science has not yet produced irrefutable proof. Work with human subjects has shown that…

[P]sychedelics are capable of rapidly promoting structural and functional neuroplasticity shortly after administration… Healthy individuals also report higher positive affect and better wellbeing, effects that can persist for months or up to a year following a double or even a single treatment course, but the underlying mechanisms of these rapid and long-lasting behavioral changes remain unclear.

The addicted individual suffers from impairments in cognitive flexibility, signaled by “the persistence of a maladaptive response and a limited exploration of novel response strategies.” To the delight of researchers, psychedelics have been shown to exert a positive influence on obsessive-compulsive disorder; on the seemingly irresistible rituals found in eating disorders; and even on substance addictions. Psychedelics can jolt a person right out of that inflexibility, shake a person loose from the illusory “solutions” that never seem to work, and open up a wide range of possible new response strategies.

What is sought, of course, is long-lasting change in mood and learning, the type of change that can lead an individual out of addiction and make that change stick. Other relevant details have also come to light:

The psychedelic-induced window of plasticity may not be the sole catalyst for behavioral shifts, but instead could be acting as a gateway that improves learning or adaptability in conjunction with the heightened influence of environmental factors… Yet, despite the suggested benefits of psychedelics on cognitive flexibility, such effects have not been thoroughly investigated.

An interesting footnote here is that similar to “door” (as in “doors of perception”), the word “gateway” has been associated with the psychedelic experience since the 60s. The implication inherent in both those terms is that an individual still retains the power of choice, regarding whether or not to pass through that portal. Many people choose to do so, leading to what the authors of this paper call “enduring behavioral changes that characterize the unique therapeutic effects of psychedelics.”

In the research area one thing that needs to happen, obviously, is diligent further investigation of the “cognitive changes that manifest in the days and weeks following psychedelic treatment to begin uncovering the lasting consequences of psychedelic intervention.” A critical knowledge gap — the authors’ phrase — affects this entire field.

By investigating the enduring structural and cognitive effects of psychedelics, we aimed to shed light on the long-term consequences of psychedelic-induced neuronal plasticity, providing valuable insights into the potential therapeutic applications of these substances.

And that’s all the researchers aim to do — figure out if indeed this stuff is any good for alleviating the enormously damaging problem of addiction. What if everybody could figure out how to enjoy their preferences in moderation, and then walk away? What a bright world this would be!

(To be continued…)

Written by Pat Hartman. First published August 30, 2024.

Source:

“Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility,” Nature.com, February 2024

Image Copyright: Andrea Koerner/Attribution 2.0 Generic