“It makes more sense to think of mitochondria as the information processors of the cell… They are equipped with a surprisingly wide variety of receptors to sense what’s going on in the cell, they integrate all this information, and they then tell the nucleus and other organelles what to do to maintain the health of the organism.”
—Martin Picard, Ph.D Columbia University professor of psychiatry and neurology
If you’ve been following along here over the last few months, the theme of The Trip Report has been “Emergent Paradigms.”
I like to think of this “season” of the newsletter as a high-level survey of scientific findings, technologies, novel trends, and newly emerging “ways of seeing” that will help us understand the shifting landscapes of health and wellbeing and, of course, tie it all back to our main theme: psychedelics.
So far we’ve looked at:
Today, we’re looking at a radically enhanced understanding of mitochondria—the so-called “powerhouse of the cell.”
This is the context in which we’ve all been taught to understand mitochondria: the small, numerous organelles within cells that produce ATP—the molecule that stores the energy that powers nearly all biological functions.
Well, it turns out that there’s a lot more to the story.
At the molecular level, mitochondria play significant roles in:
Gene expression
Cell signaling and transport
Inflammation
Synaptic transmission
At the organism level, these mitochondrial roles are implicated in nearly all disease states. That is to say, no matter what condition you look at, emerging evidence points to mitochondrial dysfunction as a cause or major contributor to the disease state.
In the same way that the predictive mind hypothesis is turning our understanding of the brain on its head, a similar paradigm is emerging in mitochondria science.
A first port of call for this new paradigm is mental health and psychiatry, a newly formed, interdisciplinary area of study called mitochondrial psychobiology.
Even more auspiciously—and of interest to you, dear reader—early research suggests a causal link between mitochondria and the effects of psychedelics.
Let’s get into it.
But first, if you’re keen on this topic, I created a GPT with several resources about mitochondria science, stress physiology, and psychedelics called MitoDelic—use it to explore this fascinating rabbit hole further!
A Mitochondrial Renaissance
The powerhouse of the cell AND the central processing unit of the cell
I would be willing to bet that the mitochondrion are the only cellular organelle that most people can recall from high school biology, other than the nucleus.
This is due to the memorable branding as the “powerhouse of the cell.”
However, in the last few years, this traditional view of the mitochondria that we all learned about has been exposed as insufficient. It turns out that mitochondria play a variety of regulatory functions that are crucial to the cell and the organism.
The main source of this research comes from Martin Picard’s Lab at Columbia University.
Perhaps, the most interesting and “paradigmy” is the research that shows how mitochondria serve as a crucial interface between the genome and the environment and orchestrating gene expression in response to stress, external stimuli and internal demands.
We might even say that, in addition to the “powerhouse of the cell,” mitochondria are also the “central processing units of the cell.”
As regulators of gene expression, mitochondria influence not only the cellular response to stress and injury but also the maintenance of cellular health and the development of disease.
Through complex signaling pathways, mitochondria communicate with the nucleus to regulate the activity of genes, effectively serving as conductors in the symphony of cellular life.
This orchestration ensures that the cell adapts efficiently to changes, protects against stress, and mediates repair mechanisms.
Picard and his colleagues have also elucidated mitochondria’s role in intercellular signaling, hormone synthesis, apoptosis, and even the regulation of synaptic transmission in neurons.
In essence, the work of Picard and his colleagues has transformed our understanding of mitochondria from isolated energy generators to dynamic entities that integrate environmental signals with genetic instructions.
This integration enables mitochondria to play a critical role in health and disease, and thus marking them key targets for potential therapeutic interventions, especially in the realm of mental health and psychiatric disorders.
As we’ll see, one such intervention may be psychedelics.
Mitochondrial Psychobiology
Where the rubber begins to hit the road for our interests is in the role that mitochondria play in the onset of and recovery from mental illness.
Picard coined the term “mitochondrial psychobiology” to describe the relationship between these ubiquitous cellular organelles and the subjective, phenomenological experience.
He proposes that how we feel and how we respond to stress can directly influence the behavior of mitochondria within our cells, as well as the inverse—the health, integrity, and function of our mitochondria play an important role in how we feel and respond to stress.
In the paper, Stress and Psychiatric Disorders: The Role of Mitochondria, Picard and colleagues note:
“The mitochondrion, well-known for its role in cellular energy production, represents a critical nexus of biological, psychological, and social factors that underlie the mechanisms and consequences of the stress response. Psychosocial factors impact biological processes through physiological systems that are highly integrated with mitochondrial functioning.”
This dynamic relationship is always ongoing, but to understand the causality more concretely, it helps to understand what happens to our energy producers and information processors during adverse early life experiences.
Adverse Childhood Experiences
A significant predictor of future mental illness is whether someone experienced Adverse Childhood Experiences (ACE) such as abuse, molestation, chronic neglect, etc.
I think many people intuitively understand how these early life traumas set the stage for problems, but considering the mitochondrial role in this process is illuminating.
Here’s how Picard describes it:
“With increased energy demands from the stress-response system, mitochondria produce increased Reactive Oxygen Species (ROS), which overwhelm the antioxidant capacity of the cells and can result in mtDNA mutations. The resulting oxidative stress has been postulated to play a role in the pathogenesis of neuropsychiatric disorders, particularly depression and dementia. In such disease processes, it is suggested that the accumulation of ROS and mtDNA mutations, among other abnormalities, causes impaired cell functioning and replication, leading to apoptosis and neuronal atrophy”
In other words, the experience of intense danger and threat causes mitochondria to ramp energy production (fight or flight), the same way that a car engine revs up during acceleration.
Just as a car uses more gas and produces more exhaust during acceleration, when the mitochondria produce increased cellular energy, they give off a greater amount of ‘exhaust’ in the form of reactive oxygen species (ROS).
However, unlike a car that emits its car into the atmosphere, the exhaust of the mitochondria is emitted into the mitochondria and the cell at a faster rate than the detoxifying pathways can clear it, thus causing damage to the mitochondrial DNA.
With damaged mitochondrial DNA, these powerhouses and information processors of the cell are severely handicapped in their capacity, and the result can sadly be a lifetime of hypervigilance, depression, anxiety, and a greater likelihood of neurological conditions.
Mitochondria Repair: A Role for Psychedelics?
Last year, Patrick Fissler, a Swiss researcher at Medical University Salzburg and colleagues published Effects of serotonergic psychedelics on mitochondria: Transdiagnostic implications for mitochondria-related pathologies which presents a novel, mitochondrial-centric perspective on the transdiagnostic benefits of these substances across a wide range of pathologies.
The paper lays out the effect of psychedelic compounds on mitochondrial biogenesis and function according to preliminary animal studies, as well as puts forward a model for understanding the transdiagnostic effects of psychedelics through the lens of mitochondria.
They note:
“We propose that serotonergic psychedelics induce transdiagnostic effects by changes in mitochondria as a subcellular mechanism, which in turn affects higher-level functioning on the cellular and organ levels….we propose that psychedelic-induced mitochondrial effects at least partially mediate the health improvements induced by psychedelics in these pathologies.”
Interesting, right?
So, of course, the question is: do psychedelics support mitochondrial repair? Is that part of how they work?
Preliminary evidence supports the idea that psychedelics facilitate the generation of mitochondria and their functional ability.
Mitochondrial Biogenesis & Function
Mitochondria biogenesis is the process of creating new mitochondria, which results in an increase in the oxidative phosphorylation capacity and reduces pathological oxidative stress. This increases the capacity to produce energy as well as the antioxidant/detoxification capacity.
Based on preliminary research animal studies, the 5-HT2A receptor is intimately associated with mitochondrial biogenesis.
One study used DOI, a hallucinogenic 5-HT2A agonist and lisuride, an non-hallucinogenic 5-HT2A agonist to evaluate impact on the mitochondrial DNA production, a marker of mitochondrial biogenesis, and found an increase in mitochondrial DNA.
As noted above, the long-established function of mitochondria is energy production (more specifically, energy conversion from food and oxygen into ATP).
In one study in rabbits, researchers found a 45% increase in ATP production in kidney cells following administration of DOI.
In one human trial (published in 1997!), researchers found a 20% increase in brain glucose metabolism 90 minutes after ingesting 15 or 20 mg of psilocybin.
So, where does this leave us?
Well, we have two—seemingly distinct—emergent paradigms afoot: one in the molecular biology of mitochondrion and their role in mental health, and another in psychedelics and their role in mental health.
It turns out they may not be such distinct fields.
This is certainly a corner of the psychedelic renaissance to keep an eye on.