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The Curious Connection Between Psychedelics and Longevity Part II
Is BDNF/TrkB Signaling the Common Pathway?
Psychedelics are interesting for at least a few reasons:
They create ineffable, revelatory, and other-worldly experiences;
They have been shown to have powerful therapeutic effects for conditions like depression, anxiety, addiction, and possibly others;
They are powerful inductors of neuroplasticity, a property that is thought to play a role in both the subjective experience and the beneficial health effects—which, if harnessed, opens a world of possibilities.
Until last week, all this was thought to be mediated by the activation of a specific serotonin receptor called the 5-HT2A receptor.
Last week, psychedelic science nerds on Twitter freaked out (myself included) about the results of a new paper in the journal Nature Neuroscience titled Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.
The commotion was caused by the finding (in mice) that both the antidepressant and neuroplastic effects of psychedelics are the result of activation of the little-known cellular receptor Tropomyosin receptor kinase B (TrkB), NOT the infamous 5-HT2A receptor, as has long been assumed (again, in mice).
From the Abstract (emphasis added):
“The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.”
Why is this a Big Deal?
This is the strongest evidence to date that the antidepressant effects of psychedelics come from the molecular neuroplastic/neurotrophic effects and not subjective experience—a controversial and polarizing topic in the field.
As the researchers demonstrated, both the neuroplastic and antidepressant effects of psychedelics persist when the 5-HT2A receptor is blocked by ketanserin, a receptor antagonist that prevents psychedelics from binding at the 5-HT2A receptor but not the TrkB receptor.
Therefore, if the neuroplastic effects are the result of activation of a different receptor system than the 5-HT2A—which is responsible for the trip—then it is evidence that the so-called “non-hallucinogenic psychedelics” may turn out to be powerful antidepressants.
In other words, if the health benefits of psychedelics come from the upregulation of BDNF1 and binding of the TrkB receptor and NOT the 5-HT2A receptor, it may shift the focus for many researchers and drug developers to this mechanistic pathway.
However, I think there is another noteworthy implication.
Psychedelics & Longevity
In late 2021, I wrote about the similarities between the fields of psychedelics and longevity in The Curious Connection Between Psychedelics and Longevity.
The main idea of that piece is, despite the, at times, overzealous hype and hyperbole abundant in both fields, they each offer novel approaches to reducing human suffering.
In the case of psychedelics, it is their potential as treatments of stubborn mental illnesses, while the field of longevity science points to a common pathway—and possibly a way of reversing—many of the age-related diseases like Alzheimer's, heart disease, certain cancers, and cognitive decline.
There are other similarities between the two fields, namely similar cultural narratives, unique funding roadblocks, and massive unmet needs, but also, as I noted (emphasis added):
“... there appears to be a mechanistic common ground between psychedelics and longevity that is worthy of exploration.
The aging process is understood as the progressive accumulation of molecular damage and the decline of the body's Defense, Repair, and Maintenance (DRM) processes.
The science of longevity and life extension is predicated on upregulating these DRM processes and reversing the damage that has been done.”
With this recent paper and the newly understood (significant) role of the BDNF/TrkB signaling pathway in the effects of psychedelics, we may have found the mechanistic common ground.
BDNF/TrkB Signaling in Aging and Longevity Science
Much of longevity science (aka biogerontology) is an attempt to better understand and thereby upregulate these DRM processes through genetic engineering and pharmaceuticals.
But DRM processes are also naturally activated by many common forms of beneficial mild stress like exercise, fasting and caloric restriction, and transient thermal stress (sauna & cold exposure).
David Sinclair, probably the world’s most well-known longevity researcher, put it this way on Twitter:
“To be the best version of yourself, mentally & physically, activate your body’s defenses against aging and other diseases…
Trick your body into thinking its survival is at stake: skip meals, lift heavy things, avoid overeating & snacking, experience hot and cold, do aerobic exercise until you’re out of breath & take supplements proven to mimic them”
Auspiciously, activation of the BDNF/TrkB signaling pathway plays a prominent role, not only in the antidepressant and neuroplastic effects of psychedelics, but also in many of the DRM processes that are the subject of longevity science, including DNA damage repair, mitochondrial function, and cellular senescence.
In Exercise as Gene Therapy: BDNF and DNA Damage Repair, the authors note:
“Emerging evidence suggests that it may be possible to enhance the inherent DNA repair capabilities of neurons through regulation of BDNF. In its mature form, BDNF…acts primarily by binding highly specifically and selectively to the TrkB receptor. Binding to TrkB sets off a series of intracellular signals that promote cell survival, and several studies have concluded that BDNF protects neurons from death and degeneration, both in vitro and in vivo.”
“Brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB are highly expressed in the cortical and hippocampal areas and play an essential role in learning and memory. The decline of cognitive function with aging is a major risk factor for cognitive diseases such as Alzheimer’s disease. Therefore, an alteration of BDNF/TrkB signaling with aging and/or pathological conditions has been indicated as a potential mechanism of cognitive decline.”
Furthermore, aberrant changes in BDNF/TrkB signaling are implicated in obesity (a major driver of pathology) and cancer:
“Unusual changes in the TrkB signaling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway.”
Researchers also found that age-related changes in the central nervous system can be counteracted by the introduction of BDNF or by increasing the expression of its receptors.
“Interestingly, recent findings show that some physiologic or pathologic age-associated changes in the central nervous system could be offset by administration of exogenous BDNF and/or by stimulating its receptor expression.
These molecules may thus represent a physiological reserve which could determine physiological or pathological aging. These data suggest that boosting the expression or activity of these endogenous protective systems may be a promising therapeutic alternative to enhance healthy aging.”
It goes without saying that there is a lot of scientific work to be done on how this all works and the implications for psychedelic use in light of this new mechanistic understanding.
But the suggestion that BDNF activation serves as a physiological reserve that greatly impacts the aging process and that psychedelics release endogenous BDNF so intensely sounds an awful lot like the proverbial fountain of youth.
Interesting, isn’t it?
In closing, I can think of at least three implications of this new insight—aside from the development of non-hallucinogenic psychedelics—at the intersection of psychedelics and longevity, including:
Can psychedelics play a role in slowing the aging process and even reversing chronic diseases?
Can psychedelics enhance the beneficial effects of exercise, fasting, cognitive challenge, and other health-promoting practices?
What does this mean for our understanding of low-dose psychedelic use, namely frequent microdosing?
As always, thanks for reading, and please let me know in the comments what you think!
BDNF stands for Brain-Derived Neurotrophic Factor, a protein that plays an important role in the growth and survival of neurons in the brain and spinal cord. BDNF is involved in many aspects of brain function, including neuronal development, synaptic plasticity (the ability of synapses to change and strengthen over time), and learning and memory. BDNF is also implicated in various neuropsychiatric disorders, such as depression, anxiety, and Alzheimer's disease.