Cover art created using OpenAI’s DALL-E image generator*

A setting sun paints the San Diegan marine clouds a pastel palette as onlookers atop a coastal bluff wait for the famous green flash. Down below on the beach two gentlemen anticipate a different flash. Both have exited their wheelchairs for seats on the sand, the beach a purposeful setting for a ritual they’ve practiced before. They’ve ingested psilocybin-containing mushrooms and, while the Pacific Southwest is surely a beautiful natural setting they might aim to reflect into the mindset they’re about to occupy, there is a more profane reason they’ve come to the beach. The sand will break their fall. As the serotonergic substance takes its effect, the men experience a change in cognition and–as can be elicited in those with paralysis from spinal cord injury–a concurrent onset of involuntary spasms in their paralyzed leg muscles. Spasms so strong they can “stand on them like crutches.” As the sun sets, they repeatedly rise on their mushroom-induced leg spasms and fall into the sand. 

An anonymous source told me this story, and while I have yet to confirm the story, I believe it anyway. My belief is informed by multiple inputs, including my relation with the source, doctoral training in spinal cord injury (SCI) physiology, convergent first-hand reports from people I know with the lived experience of SCI who have self-administered, and most importantly data I generated from research that I initiated in response to the preponderance of anecdote resonating from this community. At IPN’s PsychedelX 2023, Meghan DellaCrosse, Psy.D., incisively drew attention to the phenomenon of clinical population “comprehensively excluded from the literature” in her talk titled From Art Historian to Psychedelic Scientist: Getting to Know Your Vehicle. People with SCI are one such comprehensively excluded group, which is one reason I draw attention to them. Indeed, it is my job to use this community’s story to guide meaningful research questions, so it might be obvious why I am pointing science at the topic of fierce muscle spasms–and other non-obvious bodily responses, as we’ll see–invoked by psychedelic substances in people with SCI. But paralysis from SCI is relatively rare (national annualized incidence just below 18,000 cases), so you might be wondering why I’m blogging to a general audience about this niche neurological condition. Well, at a theoretical level, SCI is a “quasi-experimental” opportunity to observe the otherwise hidden somatic side effects of what are normally thought of as “mind-altering” substances. And from a more consequential perspective, this population is one of the first and clearest examples of a group showing a safety signal for adverse non-psychiatric responses following administration. Mapping the risk landscape of psychedelic substances is of the utmost importance during this upswing phase of knowledge generation in our field as we approach mass implementation. We have an ethical obligation to clearly inform patients of risks, and in the ethos of inclusivity, we ought to understand different states and traits that can alter the otherwise well-known safety profile of these substances. 

As a physiological primer, we’ve known since at least the 1960s that certain subtypes of serotonin receptors– the same as those in the membranes of neurons in the brain now famous for mediating effects on consciousness– are also expressed by neurons in the spinal cord. Of course, cord neurons have different functional roles than those in the brain so activation of cord neurons’ serotonin receptors leads to different outcomes. Of importance, different classes of monoamines–including tryptamines such as psilocybin–are known to have an excitatory effect on cord motor neurons, the primary (or “alpha”) neurons that send signals to muscles (Musienko et al, 2012). Other serotonergic substances have been shown to act on cord sensory neurons in an inhibitory manner implicated in pain management. Importantly, in classic spinal cord neurophysiology experiments, these serotonergic substances were studied in basic (cell) and pre-clinical (animal) models, outside the context of studying psychedelic effects. Thus, though there was evidence for efficacy, the substances fell into the translational “valley of death.” Though the physiologists and drug developers in my field rarely discuss this topic, I imagine they realized that the class of drugs they were pouring onto neurons and spinal cords in their labs had different roles in the broader human context. Roles in the domains of culture and consciousness and not the somatic motor and sensory function they were interested in. I invoke my imagination because I am of a younger generation and thus was not present for their conversations. But I did once hear a modern neuroscience faculty, when discussing a monoamine’s effect on the motor function of a cohort of spinal cord injured rodents, say “I wish we could use these as rehabilitation adjuvants in humans, but they cause hallucination.” 

This known serotonergic excitatory motor effect is one domain that informs my belief in the opening story. From the standpoint of quality of life and activities of daily living, spasms are usually a nuisance, but from the neurophysiological standpoint spasms are a serendipitous behavioral assay for the excitability of cord motor neurons. Furthermore, as someone who’s been living, working, and playing with people living with SCI since 2010, I have listened to a long list of first-hand reports from friends and acquaintances corroborating the circumstance. Although these stories don’t qualify as even circumstantial evidence, it’s my job as a scientist to take the experience that usually evaporates as an anecdote and condensate it into the data we accept as evidence. We’ll dive into those studies at the end. But first an aside on expectations. 

People living with paralysis, from SCI and other causes, have exercised their agency as fellow travelers, bought the ticket, and took the ride. They’ve done so for many of the same reasons the rest of us have, in the name of hedonism, recreation, mental health, consciousness expansion, spiritual exploration, or the simple desire to bear witness to whatever it is on the other side of the veil. One novel purpose of self-experimentation unique to this population, however, has been a pursuit of the somatic neurotherapeutic potential these substances could bestow as interventional agents of neurological change at the spinal cord level. All that talk of psychedelics inducing neuroplasticity you’ve heard about in the news: well the cord is smart too and its constituent parts are potentiated by psychedelic substances via similar underlying mechanisms that induce the supraspinal (read: brain) neural plasticity championed by Beckley Foundation’s colorful chord plot and the like. Thus, people like Devon Colbert, a tetraplegic man who has gone on the record via his social media channels and various podcast interviews, have been self-administering these substances post-SCI routinely with very keen sensitivities for the effects on somatic neurological function. In the domains of the population-specific non-psychiatric outcomes, some individual benefits have been reported, and of course, as conscious beings, the potential psychological benefits in psychiatric outcomes could apply to this population too. Of course, the story of Devon, and the unspoken stories of who-knows-how-many brave souls who aren’t sharing their lived experience in the town square, should be considered evidence of generalizable benefit in neither physiology nor psychology. But there is still a deductive truth we can derive from their reports. If psychedelic substances necessarily induced the functional neuroregeneration that is the holy grail of paralysis research, we would have heard a different story. Using this deductive logic, we can be certain that these substances by themselves will not be a cure for paralysis. But this does not mean they won’t be another arrow in the quiver of care for paralysis, restoring motor or sensory function albeit below the cure threshold (in the physiological domain) and improving quality of life (in physical and social domains). The theoretical and anecdotal circumstance I outline here sets the foundation for the potential reward that justifies the pursuit of a therapeutic, so on to doing the scientific labor of generating generalizable evidence. And as all clinical scientists know, we always begin the translation into humans with an eye for safety aiming for a robust understanding of risk. 

Those of you familiar with the pharmacology of serotonergic psychedelics are probably now correctly thinking that both toxicity and absolute contraindications are well documented. On pharmacological toxicity, these substances are physiologically safe even at doses orders of magnitude above that required for their cognitive effects: for LSD, scientific literature shows a fatal intravenous dose in mammals ranges from approximately 0.5 (rabbit) – 50 (mouse) mg/kg (Oster et al, 2023), and there is a published case report of a woman surviving 55 mg intranasal (Haden and Woods, 2020). And no doubt you’ve read accounts in books and internet forums of similar feats, taken with a grain of salt. On absolute contraindications, a small but notable subset of psychiatric diagnoses will exclude some people from even considering a try. On relative contraindications, some more common psychiatric medications have known drug-drug interactions and it is, as it should be, always at the discretion of the person administering to integrate a host of other considerations into the decision. Known fatality and contraindication were established via a slew of scientific studies that have indirectly or directly studied safety in certain populations. The aforementioned safety profiles surely apply to the general public where there have been a multitude of exploratory and mechanistic studies that employ serotonergic psychedelics not as therapeutic but as non-medical means for probing the mind and understanding consciousness. Each of these studies might not have been designed to study safety, yet still was rigorously monitored for unanticipated adverse events that are only reported in public documents if they occur (one of the few cases where an absence of proof–at least in the public domain–is proof of absence). That you didn’t hear about a safety problem indirectly means there wasn’t one. But in a clinical context, only a limited number of psychiatric diagnoses have been directly tested for safety via Phase I clinical trials. And in these populations even for a more obvious safety consideration such as hallucinogen persisting perception disorder (HPPD), the states and traits that slide the scales of risk from higher to lower are unknown. While there will always be unanticipated risks, all of the known risks mentioned above apply to people with intact/uninjured nervous systems. 

In 2020 a small group of SCI researchers convened and decided to point our professional efforts at psychedelics in this group. We began with the intent of harm reduction, knowing full well the “mushroom spasms” story–and others like it–that opened this blog post. We aimed to first map the population-specific constellation of risks in people with SCI, before moving on to the potential rewards that we knew were justified by the classic neurophysiology experiments we were brought up on. In 2021, medical student Pärham Riahi from Karolinska Institute in Stockholm, Sweden, traveled to Miami to conduct their thesis project with me on the highly anticipated risk of spasms. We relied on self-report and administered several previously validated clinical scales of short-term muscle spasticity to people with SCI who had sometime after their injury self-administered a serotonergic psychedelic. Of course, all of the limitations of self-reporting apply to the interpretation of our results. Across five separate outcomes derived from three different clinically validated scales, we saw a unanimous and robust statistical signal for both significance and effect size. Pärham successfully defended this thesis last year, concluding the intramural abstract with “this study, to our knowledge the first empirical data on the topic of the experience of people with SCI with psychedelic substances, demonstrated acute and transient spasticity after self-administration“. He presented the results at PsychedelX last year, and a scientific paper has been submitted to the Journal of Psychoactive Drugs. Since then, a broader group of physicians and researchers got together to scrape internet forms for SCI self-report of adverse signs and symptoms after self-administration. The resulting paper, published in the journal Neurotrauma Reports (Abrams et al, 2023), puts forth our hypothesis for an SCI risk phenotype that mirrors a known phenomenon called peripherally dominant serotonin syndrome (PDSS). This perspective paper has a table that outlines the risk factors we anticipate based on this hypothesis, emphasizing muscle spasms but importantly including cardiovascular and thermoregulatory risks that occur in PDSS and have been reported on forms by people with SCI after self-administration. In response to the publication of this paper, we were contacted by a practitioner of psychedelic-assisted therapies who described to us a case of one of their patients who has tetraplegia from cervical SCI and who had a serious adverse event after administration of psilocybin mushrooms that resulted in hospitalization. We are currently in the process of publishing this situation as a case report, as it exemplifies exactly the need for population-specific safety information for psychedelic substances. Before the Neurotrauma Reports paper, which came out after the therapist’s fateful session that resulted in their tetraplegic patient’s hospitalization, there was no authoritative source that could have informed them that their patient’s SCI conferred a unique and possibly substantial physiological risk that could undermine the psychological goals they were pursuing. 

Citations

Abrams SK, Rabinovitch BS, Zafar R, Aziz AS, Cherup NP, McMillan DW, Nielson JL, Lewis EC. Persons With Spinal Cord Injury Report Peripherally Dominant Serotonin-Like Syndrome After Use of Serotonergic Psychedelics. Neurotrauma Reports. 2023;4(1):543-50.

Haden M, Woods B. LSD Overdoses: Three Case Reports. J Stud Alcohol Drugs. 2020;81(1):115–8.

Musienko P, Heutschi J, Friedli L, van den Brand R, Courtine G. Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury. Exp Neurol. 2012;235(1):100-9.

Oster E, Čudina N, Pavasović H, Prevendar Crnić A, Božić F, Fadel C, Giorgi M. Intoxication of dogs and cats with common stimulating, hallucinogenic and dissociative recreational drugs. Vet Anim Sci. 2023;19:100288.

 

If you’re interested in writing for this blog, email Luke Johnson at lhjohnson1999[at]gmail.com.

*Cover image initial prompt: I need a graphic for a blog post on the Intercollegiate Psychedelics Network website. This particular blog post is about the potential of psychedelics to be used as therapeutic agents in spinal cord injury patients. Here’s the first paragraph of the blog post, use it to inspire a graphic. Successive prompts were then used to alter the initial generated image, namely to make the men in the wheelchairs younger and to try to change the wheelchairs to the rigid style of wheelchairs that are more commonly used by individuals with spinal chord injury. Unfortunately, the DALL-E image generator would not make images with any other kind of wheelchair than the folding, hospital style wheelchairs that it did. 

About The Author

David W. McMillan, Ph.D.

Dr. McMillan is an Assistant Professor for the University of Miami Leonard M. Miller School of Medicine, Department of Neurological Surgery, and Director of Education and Outreach for one of his institution’s centers of excellences called The Miami Project to Cure Paralysis. Personally and professionally committed to using research to understand, manage, and eventually cure paralysis from spinal cord injury (SCI), Dr. McMillan takes a keen interest in the effect of certain serotonergic psychedelic substances on somatic motor and sensory circuits that connect through the spinal cord. Starting from the standpoint of harm reduction he aims to meet the SCI and research communities where they stand, balancing excitement about the non-psychiatric and psychiatric therapeutic potential of these substances with a cultural background and population-specific risks unique to SCI that ought to be considered in the balance of risk and reward.

Twitter: @DrDWMcMillan
ORCID iD: 0000-0003-4167-5656

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