End of Year Psychedelic Research Review: Study #2

With everything we have all been experiencing under the onslaught of the pandemic, it’s very easy to lose track of the incredible revolution that is occurring within the realm of psychedelic research over this past year. Honestly, study after study with modern research protocols and peer review are being released and finally validating what has been anecdotally reported by word of mouth within underground communities for decades. Much of this was previously investigated in earlier research eras, but wouldn’t meet today’s rigor for RCT (randomized control trials) standards, even though the previous evidence was suggestively convincing. 

But some questions had not even been directly asked and so much of the investigative technology we enjoy now was just not available, much less conceived. We can thank the neuro-imaging revolution for much of the drive behind our current wave of psychedelic trials; think of the work of Imperial College in examining the default mode network (DMN) activity under psilocybin using fMRI studies of blood flow oxygen uptake. Those findings were actually contrary to what was speculated to be occurring within the cortex under the influence of psychedelics, requiring a revision to proposed mechanisms of action. 

One theme has been starting to emerge from the incredibly diverse and active field of study investigating conditions as divergent as fibromyalgia, alcoholism, autism, depression, chronic pain, anorexia nervosa, etc. It’s the trend line of evidence strongly pointing to a transdiagnostic mechanism of action underlying the effects of multiple compounds; LSD, psilocybin, MDMA, ketamine, ibogaine, and others. Something is changing beyond the profound psychological mechanisms that are reshaping patients perception and experience of their often severely debilitating conditions; there has been persistently increasing support that these changes are additionally occurring at a structural level as well, that is to say, within our local and global neurology. At the level of our individual neurons, brain structures and circuits, and in our neurochemical receptors distributed throughout the cortex and the body, all the profound clinical transformations have pointed to these areas as the staging ground for where the root of these changes are taking place. 

In fact, it’s caused a bit a of schism in various research camps, as well as with traditional practitioners; are the changes due to the psychedelic event (think Johns Hopkins “mystical experience” study with psilocybin) or is it due to suspected reorganization and restoration within the nervous system itself? I will assert that it’s both, with some conditions needing more of one axis than the other, but we are only at the beginning stages of establishing best practices and continuity of care, so that’s another discussion. 

But what are the neural mechanisms that drive that change and where is it occurring? Due to the type of evidence that has been accumulating, things like spinogenesis, synaptogenesis, dendritic arborization, and dendritic complexity, often proposed at the layer five level of pyramidal neurons in the prefrontal cortex, but it’s been very difficult to observe that occurring in real time in a live host, that is to say in vivo as opposed to in vitro in a petri dish. So this next study was offered up by researcher Zeus Tipado as the best study of the year, bar none, and he has a point. I personally have a different opinion and will be offering up some previously unreleased work of Dr. Gül Dölen that she presented at the Horizons Conference earlier this month in tomorrow’s post that builds on a previous study. But it’s undeniable that the name of Ling-Xiao Shao has been in the mentions of most major researchers and that his study, “Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo”, is as equally a landmark study as Imperial’s psilocybin vs escitalopram for depression trial. He was finally able to establish that psilocybin increases dendritic spine density and spine head width by 10% within 24 hours within live mice, and that the effects persisted for greater than one month and lasting up to three or four. Let’s be clear; 10% is a massive increase and for longer than a quarter year no small duration; that can be a sizable beachhead to establish mental health recovery upon with intensive integration therapy and practices.

Crucially, this increase in spine density and size in the prefrontal cortical pyramidal cells ameliorates stress-related “behavioral deficits” in mice. Stress-related behavioral deficits are the experimentally induced equivalent of depression in mice, usually caused by creating “learned helplessness” with something like a forced water swim. They were able to establish that it had dose dependence, that is to say, higher doses of psilocybin induced greater degrees of spinogenesis, up to a point. This is important because depression in humans, for all it’s starkly noticeable negative emotional impacts, is chiefly characterized neurologically by the fact that it creates atrophy in the pre-frontal cortex; actual loss of neurons in the brain. So those neuronal losses are strongly associated with a loss of ability to regulate your mood, an increased sensitivity to pain, increased challenges to normal living when your cognitive resources are decreased and absorbed in excessive iterative rumination; read: automatic negative thoughts that often continue unabatedly coloring your entire worldview and self-concept. 

If increases in spine density decrease stress-related responses in mice, that is strong evidence there is a potent antidepressant effect created by the psilocybin reversing that stress-induced atrophy in the medial prefrontal cortex, which just happens to be part of the default mode network (DMN), one of the brain circuits most implicated in the effectiveness of the psychedelic experience. Previous work had discussed the increased neuritogenesis, synaptogenesis, spinal density, and increased dendritic complexity and arborization, but it was all in vitro. 

In fact, personally, reading this earlier work was my first real glimmer of hope when I entered the NYU psilocybin trial for major depressive disorder. I had been studying neuroplasticity for years due to my work with chronic pain clients, but under the day-to-day silent, emotionally crushing experience that is treatment resistant depression, I had completely lost track of the prefrontal cortex atrophy. After reading a review study, I ran into the head of the trial the next morning on the elevator and began excited discussing the research and it’s more than “just psychological” impacts, finally exclaiming “That’s insane; that’s just insane!”. I don’t think he was used to patients geeking out and gushing over the latest developments neurology, but it was a defining moment for me to see things through in spite of any fear I had that it would be ineffective against my depression and increasingly potent suicidality.

What Ling-Xiao and his team at the Alex Kwan Lab in Yale have done, with psilocybin provided by the Usona Institute, is definitely established that this neurological transformation isn’t just speculative, and is occurring rapidly, strongly, and persistently. Likely those changes can be improved and sustained with ongoing research, creating relief for millions of sufferers that may have been facing unrelenting depression that was unresponsive to conventional and alternative treatments for sometimes decades.