Psychedelics for Brain Injury: A Mini-Review

This review (2021) explores the latest studies that use psychedelic therapeutics to treat (traumatic) brain injury (TBI). It proposed that psychedelic pharmacotherapies may fundamentally alter the future of brain injury treatment via modulation of neuroinflammation, neuroplasticity, hippocampal neurogenesis, and brain complexity. The review concludes that further phase II trials could shed more light on the mechanisms of these promising drugs and how they could treat brain injury, especially TBI and reperfusion injury from stroke.

Abstract

“Objective: 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.

Methods: Narrative mini-review of studies published related to psychedelic therapeutics and brain injury

Results: Recent in vitro, in vivo, and case report studies suggest psychedelic pharmacotherapies may influence the future of brain injury treatment through modulation of neuroinflammation, hippocampal neurogenesis, neuroplasticity, and brain complexity.

Conclusions: Historical data on the safety of some of these substances could serve in effect as phase 0 and phase I studies. Further phase II trials will illuminate how these drugs may treat brain injury, particularly TBI and reperfusion injury from stroke.”

Authors: Shariq M. Khan, Gregory T. Carter, Sunil K. Aggarwal & Julie Holland

Notes

Traumatic brain injury (TBI) is a sudden injury that causes damage to the brain. If classified as mild (mBTI) it’s usually classified as a concussion. Looking through the lens of what happens in the brain, TBI can be seen as neuroinflammation (though with an acute cause).

Neuroinflammation

Psychedelics may be helpful as they elicit a unique pattern of cytokine (proteins – important in cell signalling) expression. “[P]sychedelics 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 (e.g. psilocybin, LSD) act through influencing 5-HT(2a) (serotonin) receptors. These receptors are most pronounced in the brain (though also in the gut), and are also implicated in immunomodulation (modulation of the immune system).

The most studied psychedelics for TBI is DMT. “[I]t may be reasonable to hypothesize that DMT has some, or all, of these neuroprotective and anti-inflammatory physiologic functions as well. The only clinical trial of a selective S1R agonist for the treatment of stroke showed statistically significant functional recovery in post-hoc analysis of moderately-to-severely affected patients. DMT has been shown to reduce ischemic brain injury [not enough blood flow] after middle cerebral artery occlusion (MCAO) through S1R dependent activity in murine models.”

Hippocampal Neurogenesis

Neurogenesis – the growth of new brain cells – is influenced by the stimulation of serotonin (5HT) receptors. Research in mice show an increase in neurogenesis at low doses, but inhibition at high dosages. Using multiple low (micro) doses might be an avenue to use psychedelics for TBI.

Neuroplasticity

Neuroplasticity – forming/reorganizing synaptic connections – may hold promise for TBI but could also be a cause for complications (e.g. epilepsy). Research in those without TBI has shown that psychedelics promote neuroplasticity (Olson, 2022). Studying cells and small animals, “Ly et al. (2018) found that some psychedelics were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine in promoting plasticity.“

Increase in Brain Complexity

Disorders of consciousness (DOC) is experienced by 4 to 38% of stroke patients. Psychedelics may increase conscious awareness in these patients (Scott & Carhart-Harris, 2019). “They hypothesize psychedelics increase brain activity complexity and conscious content, in contrast to current stimulant drugs that increase arousal.“

Psychedelics are known to influence the Default Mode Network (DMN). The connectivity in the DMN is decreased for those with DOC. Alas, direct research in this area is lacking.

Conclusions

“Psychedelics may play a future role in treatment of brain injury through a variety of mechanisms. Though these are a novel class of drugs deserving close study, more data are necessary to prove their efficacy for treatment of brain injury, as historically many compounds have seemed promising in vitro, including likely hundreds of compounds thought to facilitate neuroplasticity and neuroprotection, but have not borne out in clinical trials “

If a macro (hallucinogenic) dose is necessary remains to be seen. “Extrapolating from animal studies, the doses required at least for the anti-inflammatory effects of psychedelics are predicted to be magnitudes less than threshold for hallucinations.” Research in rats, with a compound similar to MDMA, “suggest that psychedelics’ behavioral and anti-inflammatory effects may have separate, but related, underlying mechanisms.”

Finally, the authors note that depression and PTSD themselves negatively influence recovery from TBI. And, as is now much better understood, psychedelics can help here – they may also indirectly help those with TBI recover.

Summary

INTRODUCTION

Despite millennia of historical use around the world, research into medical uses of psychedelic drugs has been stymied by stigma. However, due to advances in research methodology and changes in the regulation of these substances, a scientific renaissance is occurring for these drugs.

METHODS

We conducted a literature search of articles relevant to psychedelic therapeutics for brain injury using PubMed. A narrative mini-review format was employed to provide a brief overview.

NEUROINFLAMMATION

Depression, addiction, Alzheimer’s, and Parkinson’s all appear to be linked to neuroinflammatory states. Psychedelics may represent a fourth class of anti-inflammatory drugs.

Modulation of the inflammatory response after stroke may improve recovery. However, the inflammatory response has both beneficial and harmful effects to the recovering patient, and careful regulation of the inflammatory response rather than blunt reduction of the response is critical to improved outcomes.

Because revascularization techniques are thought to be the inciting event for much of the neuroinflammatory response, combining revascularization with immunomodulation may hold promise for stroke treatment.

Psychedelics act on 5-HT2a receptors, which are found on nearly all tissue and cell types, including all major immune-related cell types. DMT has been studied for its effects on neuroinflammation and reperfusion injury.

DMT is an endogenously produced hallucinogen, but its physiologic function remains elusive. This is likely due to a paradigm in which the scientific community has assumed DMT can only be a hallucinogen. Recent experiments have shown that DMT regulates an additional receptor, S1R, which plays an important role in the immunomodulating response of DMT. S1R dysfunction is known to be involved in a wide range of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, and TBI.

DMT has been shown to reduce ischemic brain injury after middle cerebral artery occlusion through S1R dependent activity in murine models. It has also been shown to enhance functional regeneration of the affected limb in human-specific models including human cerebral organoids.

HIPPOCAMPAL NEUROGENESIS

Though hippocampal neurogenesis is associated with cognitive recovery after TBI and stroke, there is not a direct correlation between increased neurogenesis and recovery.

Psilocybin increases hippocampal neurogenesis in a non-linear fashion, with higher doses inhibiting it. However, high doses administered once-per-week avoid tolerance buildup.

NEUROPLASTICITY

Novel interventional approaches to improve functional outcomes after brain injury by inducing neural plasticity may also drive complications such as epilepsy and memory disturbance.

The search for pharmacologic agents that stimulate neuroplasticity after brain injury has thus far been inconclusive. However, recent reports demonstrate that psychedelics promote both structural and functional neuroplasticity in non-injured brains.

One hypothesis for psychedelics’ beneficial effect on neuroplasticity in brain injury is via induction of Brain-derived neurotrophic factor (BDNF), but many non-psychedelic drugs have failed to alter the course of brain injury through induction of BDNF.

Evidence suggests that S1R is an important part of the plasticity response to stroke, possibly expanding the therapeutic window for acute stroke.

Mirror visual-feedback (MVF) has been shown to enhance key features of neuroplasticity, including cross-modal cortical reorganization and learning, in patients 12 months post stroke. Psilocybin combined with MVF has been shown to reduce phantom limb pain.

INCREASE IN BRAIN COMPLEXITY

Disorders of consciousness can arise from a variety of brain injuries including trauma, hypoglycemia, anoxia, and stroke. Though many therapies have been proposed for patients with DOC, current evidence supporting their use is inconsistent.

Scott and Carhart-Harris have hypothesized that psilocybin increases brain activity complexity and conscious content, in contrast to current stimulant drugs that increase arousal. They argue that increasing conscious content, rather than arousal, as with stimulants, may be key to increasing conscious awareness in DOC patients.

Antagonism of 5HTRs is associated with reduced cognitive flexibility and increased slow-wave sleep and sedation, and is highly correlated with Glasgow Coma Scale scores in stroke patients.

CONCLUSIONS

Psychedelics may play a future role in treatment of brain injury through a variety of mechanisms, though more data is necessary to prove their efficacy. There is already mixed evidence to suggest the use of non-classical psychedelics, such as ketamine, tetrahydrocannabinol (THC) and cannabidiol, as neuroprotectants after TBI and stroke.

The subjective hallucinogenic effects of psychedelics may be necessary for some, or all, of their therapeutic effects. However, studies on the psychological effects of micro-dosing psychedelics seem to be explained by placebo effect.

Recent studies suggest that the behavioral and anti-inflammatory effects of psychedelics may have separate, but related, underlying mechanisms. The pivotal mental state hypothesis is used to explain the evolutionary function of 5-HT2a receptor agonism in inducing neurologic hyper-plasticity and psychological adaptation.

Classical psychedelics have millennia of historical use and are safe to use under close medical supervision. However, further phase II trials are needed to determine their effectiveness in treating brain injury.

The study of non-psychoactive analogs may answer fundamental questions regarding the interplay of hallucinations with other properties of psychedelic therapy, and facilitate more practical use in acute hospital settings. Psychedelics may also prove valuable in fostering recovery from brain injury from a trauma recovery rehabilitation psychology standpoint.