Traumatic Brain Injury

Key Insights

• Traumatic brain injury (TBI) is a common injury where an external force is applied to the head. Concussion is perhaps the most well-known type of TBI and is very common in athletes, military personnel as well as the general population.
• Mental health problems are common after experiencing a TBI with mood disorders like depression, anxiety and PTSD being the most common.
• Research with psychedelics is in the preclinical phase of the drug development process. Early evidence suggests that psychedelics can be used to treat TBI and related disorders on a physiological level.

What is Traumatic Brain Injury?

Traumatic brain injury (TBI) can happen when a person suffers a blow to the head that results in damage to the brain. In most cases, a blow to the head causes the brain to hit against the skull which can cause brain damage. People can suffer a TBI from something as simple as a fall, physical contact in sports as well as in car accidents. Technically speaking, TBI is an alteration in brain function, or other evidence of brain pathology, caused by an external force on the head [1]. 

TBI varies in severity and can have wide-ranging physical and psychological symptoms. The severity of TBI ranges from mild to moderate to severe, with symptoms and treatment options depending on the severity of the injury. Consequently, symptoms vary from person to person which can make diagnosis and treatment difficult.

Moreover, some symptoms may appear right away, while others may not appear for hours or days after the injury. In the case of mild TBI (mTBI), cells in the brain are affected temporarily. In contrast, more moderate to severe cases of TBI can result in torn tissues, bleeding, and other physical damage to the brain, which, if left untreated, can lead to long-term complications or even death [2].

An estimated 70 million individuals across the globe sustain a TBI each year [3]. According to the CDC, there were roughly 61,000 TBI-related deaths in the U.S. alone in 2019 [4]. Given the prevalence and severity of the outcomes associated with TBI, the annual global economic burden shouldered by TBI is an estimated US$400 billion [5].

Making matters worse, mental health problems are common after experiencing a TBI. Mood disorders like depression and anxiety are the most common psychiatric disorder after sustaining a TBI, presenting at rates higher than in the general population [6]. 

Classifying TBI

TBI can be classified into two broad categories. A number of different factors are taken into account when classifying TBI including the timing and nature of the impact (i.e., type of force), the location of the injury and lastly based on clinical severity using the Glasgow Coma Scale (GCS). The scale is scored from 3 to 15 and is based on verbal, motor and eye-opening reactions to stimuli with lower scores indicating a higher risk of mortality [7].

1. Mild Traumatic Brain Injury (mTBI)

mTBI accounts for up to 90% of all reported cases of TBI. The most common type of mTBI is a concussion, accounting for over 80% of all mTBIs [8].

In the cases of mTBI and concussion, physical symptoms include headache, nausea and vomiting, fatigue or drowsiness, problems with speech and dizziness. Sensory symptoms include blurred vision and sensitivity to light or sounds. Cognitive behavioural symptoms include the aforementioned loss of consciousness, no loss of consciousness but being in a state of confusion, memory problems, mood swings and feelings of anxiousness and depression [9].

2. Moderate to Severe Traumatic Brain Injury

Moderate to severe TBIs can include any signs and symptoms of mild injuries, although the symptoms are more pronounced. In addition to the symptoms of mTBI, a person with a moderate to severe TBI can experience a persistent headache, repeated nausea/vomiting, convulsions, dilation of one or both pupils, inability to awaken from sleep or numbness in fingers and toes. Cognitive symptoms can include profound confusion, agitation, slurred speech and in some cases, people can fall into a coma [9].

Diagnosing & Treating Traumatic Brain Injury

Diagnosing TBI can be complicated with various symptoms and classification criteria. While the GCS above provides medical professionals with reliable prognostic information, it is limited in that it does not give any information on the pathologies underlying a TBI that can be therapeutically targeted [10].

Commonly used methods include biomarkers and neuroimaging techniques like CT scans and MRI. While these techniques are invaluable, they don’t help in the immediate diagnosis given the need for high-tech equipment that is often not widely available.

Once diagnosed with traumatic brain injury (TBI), a range of treatment options exist. The initial aim of treatment is to limit the development of a secondary brain injury, such as brain swelling or infection, that may cause further damage. Additionally, providing the best possible conditions for recovery from any reversible damage that has already occurred is essential.

It is worth noting that, at present, the U.S. FDA has not cleared or approved any medicinal products that are intended to diagnose or treat TBI alone in the absence of other diagnostic tests or treatments managed by a health care provider [11].

Treatment largely depends on the patient’s recovery stage, which is divided into the acute and chronic stages. In the acute phase, the primary aim is to stabilise the patient and prevent further injury. Once stabilised, a patient is said to be in the chronic stage of recovery. In this stage, different treatment options exist and they often focus on neurological rehabilitation and physiotherapy [12].

In the case of mTBI, no specific treatment is required other than rest. It is recommended that after suffering a mTBI or concussion, a person limits activities that require thinking and mental concentration, particularly for the first few days following the injury. Not only does rest minimise stress in the brain, but it also minimises the risk of sustaining another mTBI. Over-the-counter pain relievers may also be recommended in the days that follow injury to treat headaches associated with the injury [2].

In the cases of moderate and severe TBI, emergency medical care is often required in the acute stage. Immediate treatment for someone who has suffered a severe TBI focuses on preventing death, stabilizing the person’s spinal cord, heart, lung, and other vital organ functions, ensuring proper oxygen delivery and breathing, controlling blood pressure, and preventing further brain damage [13].

In some extreme cases, surgery may be necessary depending on the nature of the injury and is a relatively uncommon occurrence.

After the acute care period of in-hospital treatment, people with severe TBI are often transferred to a rehabilitation centre where a multidisciplinary team of health care providers help with recovery.

Given the high prevalence of TBIs, the lack of effective and widely accepted treatments and the severity of the outcomes associated with such injuries, researchers must continue to explore all possible treatments to help people suffering from the immediate and long-term effects of TBI.

Psychedelics & Traumatic Brain Injury

Numerous studies have shown that psychedelics have the ability to alleviate symptoms of mental disorders like anxiety, depression, PTSD and various substance use disorders (SUDs). When treating these disorders, psychedelics are often used in tandem with psychotherapy to address these illnesses’ psychological nature. However, the exact mechanisms through which psychedelics exert their effects remain open to debate. 

Consequently, the therapeutic potential of these substances may be extended beyond the psychological and used to treat physiological aspects of many diseases and injuries. One such injury for which psychedelics hold promise is TBI.

Psychedelics including psilocybin, DMT and LSD act through serotonin (5HT) receptors, most notably the 5-HT2A receptors, leading to several changes throughout the brain [14]. MDMA also influences serotonin levels in the brain, albeit through different mechanisms. Psychedelics, through multiple mechanisms, can potentially be used to target distinct aspects of TBI.

Research into the potential role psychedelics have in treating TBI remains in the preclinical stage of the drug development process. However, based on the results of studies in cells and animal models, there are three possible ways through which psychedelics can be used to treat TBI on a biological level.

1. Targeting inflammation in the brain

Inflammation is the immune system’s response to harmful stimuli like disease and cell damage. While inflammation may be a natural response, prolonged inflammation can be harmful and has been implicated in mental and neurodegenerative disorders.

Following a TBI, the dissemination of inflammation throughout the brain has been detected within days after the primary injury and persists chronically [15]. This excess level of inflammation leads to tissue destruction rather than healing. In doing so, dysregulated inflammation is a major contributing factor to neurodegeneration, and cognitive decline is observed in people who have suffered a TBI [16].

Flanagan and Nichols suggest that certain psychedelics can diminish the inflammatory response elicited by serotonin by interacting with the 5-H2TA receptor and have been shown to elicit potent anti-inflammatory effects in animal models of inflammatory disorders.

In animal models, Attila Szabo and colleagues found that DMT’s action at sigma-1 receptors has been shown to modulate inflammation by reducing the levels of inflammation-inducing molecules including TNF-α, IL-1β and IL-6 while simultaneously increasing the secretion of the anti-inflammatory IL-10.

2. Making new connections by promoting neuroplasticity

Neuroplasticity refers to the ability of the brain to modify, change, and adapt both structure and function throughout life and in response to experience. While neuroplasticity is important for repairing damage in the CNS following an injury, it also has a vital role in learning and memory development [17].

In general, the process involves the restructuring of the connections between neurons which are known as synapses. Depending on the nature of the stimulus, the connection between neurons is strengthened, thereby amplifying the signal between the neurons or the connection is weakened.

In terms of brain injury, impact to the head often damages regions of the brain and the cells within these regions. In an attempt to repair any damage, the brain may signal to strengthen the connection between synapses in specific areas while weakening the signal elsewhere

It has been proposed that psychedelics exert their therapeutic effects observed in treating mental disorders by inducing neuroplasticity through action at the 5-HT2A receptor [18].

An in vivo study found that psilocybin promotes the growth of synapses and strengthens the signal between them by increasing the density of dendritic spines. This study also found that some psychedelics were more effective (e.g. MDMA) or more potent (e.g. LSD) at promoting plasticity when compared to ketamine.

3. Promoting neurogenesis

Neurogenesis is the process by which new neurons are formed in the brain. Brain injuries, including TBI and stroke, have been shown to affect neurogenesis in a brain region known as the hippocampus, which plays a major role in learning and memory

Some have speculated that the ability of psychedelics to induce neurogenesis may be used to help treat aspects of brain injury. With serotonin receptor activation considered to have a key role in neurogenesis, serotonergic psychedelics (i.e. psychedelic that acts on these receptors), have been shown to promote neurogenesis [18]. 

In an in vivo study, mice treated with psilocybin were shown to respond to fear more quickly than untreated mice, which researchers accredited to neurogenesis. Moreover, it was found that psilocybin had a dose-dependent effect on neurogenesis, with a low dose increasing, and a high dose decreasing neurogenesis [19].

Overall, psychedelics have the potential to treat TBI via numerous physiological mechanisms. By downregulating the inflammatory response and promoting neuroplasticity and neurogenesis, psychedelics can help repair the damaged brain and decrease the likelihood of developing any long-term complications.

Psychedelic Companies & Traumatic Brain Injury

While this aspect of psychedelic science remains underexplored, a number of companies are focusing their attention here.

Lobe Sciences is a life sciences company focused on researching and developing psychedelic medicines. The company is currently developing a microdosing protocol whereby sub-perceptual doses of psilocybin or MDMA will be administered in tandem with N-acetylcysteine (NAC) to treat both mTBI and PTSD. Given that NAC is a well-known dietary supplement, its anti-inflammatory effects should complement the neuroprotective effects of psychedelics when administered together.

At Wesana Health, they are investigating the potential of psilocybin used in tandem with CBD to treat mTBI and TBI associated symptoms. In animal models of mTBI, the company’s proprietary psilocybin candidate protocol SANA-013 has demonstrated effectiveness in mice. As opposed to a single high dose of psilocybin, SANA-013 is initially administered in a relatively high ‘loading’ dose followed by self-administered maintenance doses of psilocybin and CBD to provide more sustained effects and benefits over time (Bloomberg, 2022).

In 2020, Braxia Scientific acquired Tassili Life Sciences who were working in partnership with the University of Miami to develop effective psilocybin-based treatments for PTSD and mild traumatic brain injuries (mTBI) (Lutz, 2020).

In March 2021, Revive Therapeutics released the topline results of a preclinical study evaluating the efficacy of psilocybin in treating mTBI in a rodent model. They successfully demonstrated the potential of psilocybin to restore normal cognitive functioning following mTBI (BioSpace, 2021).

In partnership with Atai Life Sciences, Neuronasal working toward repurposing N-acetylcysteine (NAC) and creating an intranasal delivery system to treat concussions.

With many companies in the psychedelic space focused on using their potential to treat mood disorders, this area of psychedelic science is truly in its infancy. As research progresses, we anticipate more companies will begin to explore the physiological effects of psychedelics and their potential in treating TBI and beyond.

References

1. Menon, D., Schwab, K., Wright, D., & Mass, A. (2010). Position Statement: Definition of Traumatic Brain Injury. Archives of Physical Medicine and Rehabilitation. https://doi.org/10.1016/j.apmr.2010.05.017

2. Mayo Clinic. (n.d). Traumatic Brain Injury. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/traumatic-brain-injury/symptoms-causes/syc-20378557

3. Dewan, M., Rattani, A., Gupta, S., Baticulon, R., Hung, Y.-C., Punchak, M., . . . Park, K. (2018). Estimating the global incidence of traumatic brain injury. Journal of Neurosurgery. https://doi.org/10.3171/2017.10.jns17352

4. CDC. (n.d). Traumatic Brain Injury & Concussion. Centers for Disease Control and Prevention. https://www.cdc.gov/traumaticbraininjury/get_the_facts.html

5. European Brain Injury Consortium. (2017). Traumatic Brain Injury. European Brain Injury Consortium. https://www.center-tbi.eu/files/news/21571f81-20b8-4860-a3dd-1f6e27d02b3d.pdf

6. Ponsford, J., Alway, Y., & Gould, K. (2018). Epidemiology and Natural History of Psychiatric Disorders After TBI. The Journal of Neuropsychiatry and Clinical Neurosciences. https://doi.org/10.1176/appi.neuropsych.18040093

7. BMJ Best Practice. (2022). Evaluation of traumatic brain injury, acute. British Medical Journal. https://bestpractice.bmj.com/topics/en-us/515

8. Leo, P., & McCrea, M. (2016). Epidemiology. In D. Laskowitz, & G. Grant, Translational Research in Traumatic Brain Injury. Boca Raton FL: Taylor and Francis Group. https://www.ncbi.nlm.nih.gov/books/NBK326730/

9. National Institute of Health. (2019). Mental health disorders common following mild head injury. National Institute of Health. https://www.nih.gov/news-events/news-releases/mental-health-disorders-common-following-mild-head-injury#:~:text=A%20new%20study%20reveals%20that,up%20care%20for%20these%20patients.

10. Gan, Z., Stein, S., Swanson, R., Guan, S., Garcia, L., Mehta, D., & Smith, D. (2019). Blood Biomarkers for Traumatic Brain Injury: A Quantitative Assessment of Diagnostic and Prognostic Accuracy. Frontiers in Neurology. https://doi.org/10.3389/fneur.2019.00446

11. U.S. Food & Drug Administration. (n.d). Traumatic Brain Injury: What to Know About Symptoms, Diagnosis, and Treatment. U.S. Food & Drug Administration. https://www.fda.gov/consumers/consumer-updates/traumatic-brain-injury-what-know-about-symptoms-diagnosis-and-treatment

12. Physiopedia. (n.d). Overview of Traumatic Brain Injury. Physiopedia. https://www.physio-pedia.com/Overview_of_Traumatic_Brain_Injury

13. National Institute of Neruological Disorders and S. (2020). Traumatic brain injury: Hope through research. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Traumatic-Brain-Injury-Hope-Through

14. Carhart-Harris, R. (2019). How do psychedelics work? Current Opinion in Psychiatry. https://blossomanalysis.com/papers/how-do-psychedelics-work/

15. Shi, K., Zhang, J., Dong, J.-f., & Shi, F.-D. (2019). Dissemination of brain inflammation in traumatic brain injury. Cellular & Molecular Immunology. https://doi.org/10.1038/s41423-019-0213-5

16. Russo, M., & McGavern, D. (2017). Inflammatory neuroprotection following traumatic brain injury. Science, 783-785. https://dx.doi.org/10.1126%2Fscience.aaf6260

17. Voss, P., Thomas, M., Cisneros-Franco, M., & de Villers-Sidani, E. (2017). Dynamic Brains and the Changing Rules of Neuroplasticity: Implications for Learning and Recovery. Frontiers in Psychology. https://doi.org/10.3389/fpsyg.2017.01657

18. de Vos, C., Mason, N., & Kuypers, K. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in Psychiatry. https://doi.org/10.3389/fpsyt.2021.724606

19. Catlow, B., Song, S., Paredes, D., Kirstein, C., & Sanchez-Ramos, J. (2013). Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Experimental Brain Research, 481-91. https://doi.org/10.1007/s00221-013-3579-0