When Psychedelics Meet an Injured Spinal Cord – What Really Happens?
We’re coming up on the anniversary of our 2023 publication on Spinal Cord Injury & Psychedelics!
To mark the occasion, I’m breaking the paper down into its most fascinating insights, shared in a way that’s easy to follow and understand.
Full paper HERE
Peripherally Dominant Serotonin-Like Syndrome in Persons With SCI Using Serotonergic Psychedelics
In able-bodied individuals, classical serotonergic psychedelics (e.g., psilocybin, LSD) exert their primary therapeutic effects via agonism of cortical 5‑HT2A receptors. However, in persons with spinal cord injury (SCI), maladaptive neuroplastic changes occur caudal to the lesion, including loss of descending serotonergic input and upregulation of postsynaptic 5‑HT receptor subunits — particularly 5‑HT2A receptors — on spinal interneurons and α-motor neurons. This receptor hypersensitivity is a compensatory response to chronic serotonergic denervation.
Here’s what this means:
In people with spinal cord injury (SCI), something different can happen when taking serotonergic psychedelics like psilocybin or LSD: an intense peripheral reaction in the body that can look a lot like a mild or localized form of serotonin syndrome.
And perhaps this is why:
After SCI, the normal serotonin “supply lines” from the brain to the spinal cord are cut or reduced.
In response, the body adapts with increased excitability of α-motor neurons at the spinal level.
This means an increase in the number (and sensitivity) of serotonin receptors in parts of the nervous system below the injury
So when someone with SCI takes a serotonergic psychedelic, those extra-sensitive peripheral serotonin receptors (especially 5-HT2A receptors on motor neurons and muscle-related pathways) get overstimulated.
So what happens?
The result is strong muscle spasms, clonus (rhythmic jerking), sweating, temperature swings, and sometimes spikes in blood pressure or heart rate, even if the mental effects of the psychedelic feel similar to someone without SCI.
Think of it like having an overactive volume knob on your muscles and autonomic system: for most people, the “dose” is just right, but for someone with SCI, the same dose can crank the peripheral effects up to uncomfortable or even risky/life threatening levels.
The resultant clinical picture shares phenomenological overlap with serotonin syndrome (SS) — namely, a triad of neuromuscular hyperactivity, autonomic hyperactivity, and preserved mental status — but appears to be peripherally dominant and population-specific to SCI. This is distinct from the centrally mediated cognitive and affective changes that remain qualitatively similar to non-SCI psychedelic users.
The pathophysiological model can be summarized as:
SCI → serotonergic denervation below lesion → receptor upregulation/hypersensitivity (5‑HT2A).
Psychedelic administration → direct 5‑HT2A agonism in periphery + CNS.
Peripheral hypersensitivity → exaggerated neuromuscular and autonomic responses.
Given the overlap with autonomic dysreflexia (AD) in high lesions (≥T6), additional caution is warranted, as psychedelic-induced sympathetic activation could exacerbate cardiovascular instability.
This highlights the need to consider dose adjustments, premedication protocols, and targeted clinical monitoring for this population, and, in some cases, to recognize that individuals with SCI may be ineligible for serotonergic psychedelic therapy due to elevated risk.
As documented in numerous firsthand accounts referenced in our paper, episodes of intense spasticity and rigidity can, paradoxically, enable muscles weakened by paralysis to momentarily support body weight — even allowing for standing or walking in cases of incomplete spinal cord injury. It is important to emphasize that this phenomenon is a pharmacological effect of the psychedelic, not evidence of neuroregeneration.
Whether neuroplasticity‑enhancing compounds like psychedelics might accelerate recovery or aid in regaining function after injury remains a compelling and evolving area of research.
To all practitioners and facilitators out there, screen your patients for SCI, and make informed, educated, safe clinical decisions.
Full paper HERE
Art by Real Fun Wow
