Brain Atrophy & Psychedelics

Among the primary causes of impairment are stroke and traumatic brain injury (TBI). Nearly half of individuals with severe TBI who need hospitalization still have significant disability even after undergoing rehabilitation. Pharmacologic treatment of brain damage is still a science in its infancy despite decades of research.

The use of psychedelic medicines for the treatment of brain injury has just entered clinical studies. This succinct overview will provide a summary of the state of research as it relates to neuro-rehabilitation and serve as a guide for individuals interested in learning more about the historical context of the current clinical studies.

Introduction

Despite psychedelic substances’ long history of use, stigma has for years prevented studies into their potential medical applications. “Classical” psychedelic substances include mescaline, lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine, which are the most well-known and culturally significant psychedelics (DMT).

• Although psychedelics have a diverse spectrum of molecular structures and target receptors, they are all capable of producing noticeable changes in sensory perception, consciousness, the experience of time, and reality.
• Though these substances are known to operate at different receptors, evidence suggests that activation of 5-HT2A receptors, a kind of excitatory serotonin or 5-HT receptors, is the common mechanism for the psychological experience of classical psychedelics.

However, because of improvements in research technique and modifications in the laws governing these substances, psychedelics are currently going through a scientific renaissance. Psilocybin and DMT trials for stroke and disorders of consciousness are expected to start in the next several years.

Psychedelics may affect the future of brain injury treatment in both the acute and chronic stages through a number of processes, including control of neuroinflammation, neuroplasticity, hippocampal neurogenesis, and increases in brain complexity, according to invitro and in vivo research.

Neurophysiology

Alzheimer’s, Parkinson’s, addiction, and depressive disorders all seem to be correlated with neuroinflammatory states in the brain. Non-steroidal anti-inflammatory drugs (NSAIDs), steroids like prednisone, and biologics that “soak up” inflammatory cytokines are the three primary kinds of anti-inflammatory medications currently available. The fourth class of anti-inflammatory drugs may include psychedelics.

After a stroke, neuroinflammation is in charge of remodeling and healing as well as infarct expansion. New medicines are actively aiming to modify this inflammation. It is believed that reperfusion injury is a major contributor to the inflammatory response to ischemic stroke. There aren’t many standard medical treatments for reperfusion injury following a stroke.

Immune cells that have been exposed to a stroke interact with neurons and microglia in the wounded tissue. The key to stroke recovery may lie in controlling this inflammatory response, particularly through the use of TNF, IL-1, IL-6, and IL-10.

• The cytokine response to brain injury, however, is likely to have both advantageous and detrimental consequences on the recovering patient. Psychedelics induce a distinct pattern of cytokine expression that favors anti-allergic conditions, in contrast to steroids, which cause widespread systemic immunosuppression.

In other words, psychedelics could be able to target a lot of pathologic immune responses without putting the body at risk of total immune suppression (like a major infection) or probable adverse effects from biologics that are already on the market (e.g., malignancy and cardiovascular disease). Rather, careful control of the inflammatory response is preferable.

• For their psychological effects, traditional psychedelics primarily affect the 5-hydroxytryptamine receptors (5-HTRs), most specifically the 5-HT2a receptor. It is generally recognized that these receptors have the ability to control peripheral and central nervous system inflammation. In actuality, the 5-HT2a receptor is the serotonin receptor that is most abundantly expressed throughout the human body.

It is found on almost every type of tissue and cell, including the majority of immune-related cell types. The brain has the highest concentration of 5-HT2a receptors, though. N,N-Dimethyltryptamine (DMT) has been particularly well-studied with regard to its effects on neuroinflammation and reperfusion injury.

• Although 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), DMT has been

Neurogenesis of the Hippocampus

In mouse models, TBI and stroke impact hippocampus neurogenesis. Although hippocampal neurogenesis is understood to play a crucial role in cognitive recovery following a stroke or traumatic brain injury, there is no direct link between enhanced neurogenesis and recovery. The type of injury, the timing of the intervention, how the cells integrate into the hippocampus circuits, and whether the goal of the intervention is greater neuronal proliferation or increased survival are all complicating considerations. Hippocampal neurogenesis is linked to enhanced cognition, relief from depression, and the encoding of episodic memory following TBI, but it is also linked to pro-epileptogenic alterations and a decline in spatial memory.

Although numerous factors are thought to contribute to hippocampus neurogenesis, 5HTR activation is one of the most crucial. Mice given acute psilocybin treatment experience non-linear changes in hippocampus neurogenesis. Higher doses impede neurogenesis whereas lower amounts promote it.

• However, once-weekly administration of large doses of psilocybin has also been associated with enhanced neurogenesis, avoiding the problem of rapid tolerance development through 5HTR downregulation. An expanding field of research is the treatment of brain damage and other mental and neurologic problems by focusing on hippocampal neurogenesis.

Neuroplasticity

Recent studies have shown that psychedelics enhance non-damaged brains’ structural and functional neuroplasticity. It has been suggested that this neuroplastic adaptation is what causes the lasting symptom improvement in psychiatric diseases following the intake of psychedelics. Ly et al. discovered that some psychedelics were more effective (like MDMA) or more potent (like LSD) at increasing plasticity than ketamine. Both non-human vertebrates and invertebrates were used to demonstrate similar findings in vivo, indicating that these systems are evolutionarily conserved.

Brain Complexity

Trauma, hypoglycemia, anoxia, and stroke are just a few of the different types of brain traumas that can result in disorders of consciousness (DOC). The main mechanism by which psychedelics are thought to increase brain complexity is via 5HTRs.

• As was previously mentioned, 5HTR agonism promotes neuroplasticity, whereas antagonism decreases cognitive flexibility and promotes drowsiness and slow-wave sleep. Additionally, it has been established that 5HTRs are crucial in the regulation of the thalamo-frontal connection, which is crucial for consciousness.

Summation

Psychedelics might one day be used to cure brain damage via a number of different processes. Traditional psychedelics have a long history of use, carry a low risk of dependence, and are safe to use when accompanied by careful medical supervision.

Even though it’s important to exercise caution when extrapolating the relevance of the aforementioned animal experiments to clinical conditions in people, this historical information should be treated as phase (0) and phase (1) investigations.

• The trial safety data may need to be reproduced with continuous, regular doses, while it is likely that a large portion of this historical data is based on intermittent, occasional dosing. Phase II trials that are conducted in more depth will shed light on how these medications may be used to treat brain injury, including TBI and reperfusion injury from stroke.