Psychedelics as Neuroplastic Agents to Treat Brain Injury

Few diseases have the propensity to cause such profoundly debilitating and life threatening effects as diseases of the brain, and stroke is one such example of a devastating brain injury, in which the interruption of cerebral blood flow rapidly causes cerebral dysfunction. Psychedelic drugs offer a tantalising new avenue for stroke rehabilitation research, offering promising neuroprotective and neuroregenerative effects, but their profound alterations to consciousness limit their use as therapeutic agents outside the clinical psychotherapeutic environment. In this investigation, we propose a novel method for administering psychedelic compounds in locally high concentrations within the stroke-injured brain using focused ultrasound, with the aim of maximising brain recovery without invoking the brain-wide changes responsible for the psychedelics' classical psychological effects.

The two main types of stoke are ischemic and hemorrhagic stroke, having an incidence rate of around 85% to 15% respectively and combined they account for around 13.7 million new strokes annually worldwide. An ischemic attack occurs when blood flow to an area of brain tissue is interrupted, typically from a blood clot blocking the passage of blood through an artery. This not only starves the affected brain region of oxygen but also of glucose, as well as preventing the removal of potentially toxic metabolic waste products such as carbon dioxide and lactic acid, causing complex biochemical changes within cells. The mechanisms of ischemic damage are manifold, involving complex metabolic events and immune responses leading eventually to neuronal cell death, neuroinflammation and the breakdown of the blood brain barrier. The resulting sequelae vary depending on the location and duration of the ischemia, but typical symptoms include sensory loss and motor dysfunction typically in the face and limbs contralateral to the hemisphere of the infarction, language processing and speech difficulties, emotional dysregulation and cognitive impairment.

The oxygen and glucose requirements of the brain are disproportionately large relative to other tissues, such that the human brain typically only makes up around 2% of total body mass but consumes approximately 20% of the total oxygen. The large metabolic requirements of the brain highlight the need for a constant robust blood supply, and whilst mechanisms exist to alleviate changes in local blood flow to compensate for changes in systemic blood pressure and local metabolic requirements, a failure of these mechanisms results in rapid and often non-reversible cellular changes. In order to maintain the generation of action potentials, 70% of the ATP consumed by the brain is used by Na+/K+ ATPase ion
pumps in maintaining the ion gradient across neuronal cell membranes. Within minutes following hypoxia, ATP supplies within the brain are depleted causing Na+/K+ pump failure, resulting in membrane depolarisation and an increase in intracellular calcium. Increased intracellular Ca2+ concentration leads to stress responses within cells which involves the release of excitatory neurotransmitters and mitochondrial dysfunction which leads to the generation of reactive oxygen species (ROS). Damage to the blood brain barrier may also occur due to the increase in ROS and cytokines, enabling protein and water into the extra cellular space, increasing the risk of vasogenic oedema and haemorrhagic transformation. In the sub-acute stage, hours to days later, apoptotic and inflammatory pathways are initiated and an infarct core is formed. Whilst the cell damage in this region may be nonrecoverable, the at-risk tissue surrounding the infarct making up the so-called penumbra, may be recoverable with appropriate reperfusion and pharmacological intervention.