Stroke and traumatic brain injury (TBI) are among the leading causes of disability. Even after engaging in rehabilitation, nearly half of patients with severe TBI requiring hospitalization are left with major disability. Despite decades of investigation, pharmacologic treatment of brain injury is still a field in its infancy.
Recent clinical trials have begun into the use of psychedelic therapeutics for treatment of brain injury. This brief review aims to summarize the current state of the science’s relevance to neurorehabilitation and may act as a resource for those seeking to understand the precedence for these ongoing clinical trials.
Despite millennia of historical use around the world, research into medical uses of psychedelic drugs has been stymied for years by stigma. “Classical” psychedelic drugs refer to the most well studied and culturally significant psychedelics, including mescaline, lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT). Though having a wide range of molecular structures and target receptors, psychedelics are unified by their ability to produce marked alterations in sensory perception, consciousness, distortion of time, and perception of reality. Evidence suggests that activation of 5-HT2A receptors (a class of excitatory receptors of serotonin or 5-HT), is the common mechanism for the psychological experience of classical psychedelics, though these compounds are known to act at other receptors.
Currently, however, psychedelics are experiencing a scientific renaissance due to advances in research methodology and changes in the regulation of these substances. Trials of psilocybin for disorders of consciousness, and DMT for stroke, are in discussion to begin in coming years. In vitro and in vivo studies suggest psychedelics may influence the future of brain injury treatment in both the acute and chronic phases through a variety of mechanisms including modulation of neuroinflammation, neuroplasticity, hippocampal neurogenesis, and increases in brain complexity.
Within the brain, depression, addiction, Alzheimer’s, and Parkinson’s all appear to be linked to neuroinflammatory states. There are currently three main classes of anti-inflammatory drugs: non-steroidal anti-inflammatory drugs (NSAIDs), steroids such as prednisone, and biologics which act like sponges to “soak up” inflammatory cytokines. Psychedelics may represent a fourth class of anti-inflammatory drugs.
Neuroinflammation after stroke is responsible for both infarct expansion as well as remodeling and repair. Modulation of this inflammation is currently a target for new therapies. The inflammatory response to ischemic stroke is thought to derive largely from reperfusion injury. In general, there are no conventional medical therapies addressing reperfusion injury after stroke.
After a stroke, immune cells invade the injured tissue, interacting with microglia and neurons. Modulating this inflammatory response, particularly through tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-10, may be the next frontier in stroke recovery. However, it should be expected that the cytokine response to brain injury has both beneficial and harmful effects to the recovering patient. In contrast to steroids, which cause generalized systemic immunosuppression, psychedelics produce a unique pattern of cytokine expression favoring anti-allergic conditions. In other words, psychedelics may target many of the pathologic immune responses without exposing the body to the risks of total immune suppression (e.g., serious infection) or potential side effects of existing biologics (e.g., malignancy and cardiovascular disease). Instead, careful regulation of the inflammatory response, rather than blunt reduction of the response, or “single-target” approaches, is critical to improved outcomes.
Classical psychedelics act principally on the 5-hydroxytryptamine receptors (5-HTRs) to produce their psychological effects, specifically the 5-HT2a receptor. These same receptors are well-known to have the potential to regulate inflammation within the central nervous system and peripherally. In fact, the 5-HT2a receptor is the most widely expressed serotonin receptor throughout the human body. It is present on nearly all tissue and cell types, including all major immune-related cell types. However, the highest density of 5-HT2a receptors is found in the brain. Though peripheral immunomodulation has been documented with other psychedelics like lysergic acid diethylamide (LSD), 3,4-methylenedioxy-methamphetamine (MDMA), and 2,5-dimethoxy-4-iodoamphetamine (DOI), N,N-Dimethyltryptamine (DMT) has been especially well-studied with regards to its effects on neuroinflammation and reperfusion injury.
TBI and stroke alter hippocampal neurogenesis in murine models. Though hippocampal neurogenesis is recognized as an important component of cognitive recovery from TBI and stroke, there is not a direct correlation between increased neurogenesis and recovery. Complicating factors include the nature of the injury, the timing of intervention, how the cells integrate into the hippocampal circuits, and whether the target of intervention is either increased neuronal proliferation or increased survival. While hippocampal neurogenesis after TBI is implicated in improved cognition, relief from depressed mood, and encoding of episodic memory, it is also associated with pro-epileptogenic changes and spatial memory impairment.
Though many factors are implicated in hippocampal neurogenesis, one of the most important is 5HTR stimulation. Acute administration of psilocybin to mice alters hippocampal neurogenesis in a non-linear fashion. Low doses lead to increased neurogenesis while higher doses inhibit it. However, increased neurogenesis has also been seen when high dose psilocybin was administered once-per-week, avoiding the issue of rapid tolerance buildup via 5HTR downregulation. Targeting hippocampal neurogenesis for treatment of brain injury and other psychiatric and neurologic disorders is an emerging area of research.
Recent reports demonstrate that psychedelics promote both structural and functional neuroplasticity in non-injured brains. The persistent symptom improvement in psychiatric disorders with administration of psychedelics has been proposed to be driven by this neuroplastic adaptation. Ly et al, found that some psychedelics were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine in promoting plasticity. These results were demonstrated in vivo in both non-human vertebrates and invertebrates, suggesting that these mechanisms are evolutionarily conserved.
Increase in Brain Complexity
Disorders of consciousness (DOC) can arise from a variety of brain injuries including trauma, hypoglycemia, anoxia, and stroke. Psychedelics are thought to increase brain complexity primarily through 5HTRs. As previously discussed, 5HTR agonism is associated with increased neuroplasticity, while antagonism is associated with reduced cognitive flexibility and increased slow-wave sleep and sedation. Secondarily, 5HTRs have been shown to play an important role in the control of thalamo-frontal connectivity, known to be important for consciousness.
Psychedelics may play a future role in treatment of brain injury through a variety of mechanisms. Classical psychedelics have millennia of historical use, do not have significant risk of dependence, and are safe to use under close medical supervision. Though there should be caution in over-interpreting the relevance of the aforementioned animal studies’ relevance to human pathological states, this historical data should serve in effect as phase 0 and phase (1) studies. However, presumably much of this historical data is based on intermittent, infrequent dosing, so trial safety data may need to be repeated with continuous, regular doses. Further phase II trials will illuminate how these drugs may treat brain injury, particularly TBI and reperfusion injury from stroke.
Further study and design of non-psychoactive analogs may answer fundamental questions regarding the interplay of hallucinations with other properties of psychedelic therapy, as well as facilitate more practical use in acute hospital settings.