Category Archives: Brain Trauma

Role of 5HT1A Receptors in the Neuroprotective and Behavioral Effects of Cannabidiol in Hypoxic-Ischemic Newborn Piglets

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“Background: Hypoxic-ischemic (HI) insults have important deleterious consequences in newborns, including short-term morbidity with neuromotor and cognitive disturbances. Cannabidiol (CBD) has demonstrated robust neuroprotective effects and shows anxiolytic/antidepressant effects as well. These effects are thought to be related to serotonin 5-HT1A receptor (5HT1AR) activation. We hereby aimed to study the role of 5HT1AR in the neuroprotective and behavioral effects of CBD in HI newborn piglets. 

Methods: 1-day-old piglets submitted to 30 min of hypoxia (FiO2 10%) and bilateral carotid occlusion were then treated daily with vehicle, CBD 1 mg/kg, or CBD with the 5HT1AR antagonist WAY 100635 1 mg/kg 72 h post-HI piglets were studied using amplitude-integrated EEG to detect seizures and a neurobehavioral test to detect neuromotor impairments. In addition, behavioral performance including social interaction, playful activity, hyperlocomotion, and motionless periods was assessed. Then, brain damage was assessed using histology (Nissl and TUNEL staining) and biochemistry (proton magnetic resonance spectroscopy studies. 

Results: HI led to brain damage as assessed by histologic and biochemistry studies, associated with neuromotor impairment and increased seizures. These effects were not observed in HI piglets treated with CBD. These beneficial effects of CBD were not reversed by the 5HT1AR antagonist, which is in contrast with previous studies demonstrating that 5HT1AR antagonists eliminated CBD neuroprotection as assessed 6 h after HI in piglets. HI led to mood disturbances, with decreased social interaction and playfulness and increased hyperlocomotion. Mood disturbances were not observed in piglets treated with CBD, but in this case, coadministration of the 5HT1AR antagonist eliminates the beneficial effects of CBD. 

Conclusion: CBD prevented HI-induced mood disturbances in newborn piglets by acting on 5HT1AR. However, 5HT1AR activation seems to be necessary for CBD neuroprotection only in the first hours after HI.”

https://pubmed.ncbi.nlm.nih.gov/35924056/

“Postinsult CBD administration prevented HI-induced brain damage, and neuromotor deficits and behavioral disturbances. These results indicate that, in addition to its robust neuroprotective effects, CBD could be an interesting candidate to be included in the treatment of HI newborns to mitigate the consequences of stress derived from brain damage and hypothermia treatment.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.925740/full

Effects of phytocannabinoids on heart rate variability and blood pressure variability in female post-concussion syndrome patients: case series

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“Cannabidiol (CBD) can exert neuroprotective effects without being intoxicating, and in combination with Δ9-tetrahydrocannabinol (THC) CBD has shown to protect against THC psychosis. Acute concussion and post-concussion syndrome (PCS) can result in autonomic dysfunction in heart rate variability (HRV), but less information is available on blood pressure variability (BPV). Furthermore, the effects of phytocannabinoids on HRV and BPV in PCS are unknown. The purpose of this study was to observe the influence of daily administration of CBD or a combination of CBD and THC on HRV and BPV parameters in four female PCS participants. Participants completed a seated 5-min rest followed by six breaths-per-minute paced breathing protocol. Data was collected prior to phytocannabinoid intake and continued over 54 to 70 days. High frequency systolic BPV parameter increased every assessment period, unless altered due to external circumstances and symptoms. HRV parameters showed less consistent and varying responses. These results suggest that CBD can help to improve the altered autonomic dysfunction in those with PCS, and that responses to the drug administration was individualized. Double blinded, randomized controlled trials with greater sample sizes are required to better understand the influences of the varying dosages on human physiology and in PCS.”

https://pubmed.ncbi.nlm.nih.gov/34597522/

Thromboembolic Outcomes in Tetrahydrocannabinol-Positive Trauma Patients With Traumatic Brain Injury

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“Introduction: Traumatic brain injury (TBI) is a significant source of morbidity and mortality in the United States. Recent shifts in state legislation have increased the use of recreational and medical marijuana. While cannabinoids and tetrahydrocannabinol (THC) have known anti-inflammatory effects, the impact of preinjury THC use on clinical outcomes in the setting of severe TBI is unknown. We hypothesized that preinjury THC use in trauma patients suffering TBI would be associated with decreased thromboembolic events and adverse outcomes.

Methods: The American College of Surgeons Trauma Quality Improvement Program was used to identify patients aged ≥18 y with TBI and severe injury (Injury Severity Score ≥ 16) in admit year 2017. Patients with smoking or tobacco history or missing or positive toxicology tests for drug and/or alcohol use other than THC were excluded. Propensity score matching was used to compare THC+ patients to similar THC- patients.

Results: A total of 13,266 patients met inclusion criteria, of which 1669 were THC+. A total of 1377 THC+ patients were matched to 1377 THC- patients. No significant differences were found in in-hospital outcomes, including mortality, length of stay, cardiac arrest, pulmonary embolism, deep vein thrombosis, or acute respiratory distress syndrome. No patients had ischemic stroke, and THC+ patients had significantly decreased rates of hemorrhagic stroke (0.5% versus 1.5%, P = 0.02, odds ratio 0.41 [95% confidence interval 0.18-0.86]).

Conclusions: Preinjury THC use may be associated with decreased hemorrhagic stroke in severely injured patients with TBI, but there was no difference in thromboembolic outcomes. Further research into pathophysiological mechanisms related to THC are needed.”

https://pubmed.ncbi.nlm.nih.gov/35305485/

“THC linked to lower hemorrhagic stroke risk in people with traumatic brain injury”

https://vancouversun.com/cannabis-news/thc-use-may-be-associated-with-lower-hemorrhagic-stroke-risk-in-people-with-traumatic-brain-injury/wcm/a3ae3f22-2b3f-439f-987d-6364c7425eb8/amp/

Administration of Δ 9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function

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“Hypothesis: Administration of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) will enhance brain repair and improve short-term spatial working memory in mice following controlled cortical impact (CCI) by upregulating granulocyte colony-stimulating factor (G-CSF) and other neurotrophic factors (brain-derived neurotrophic factor [BDNF], glial-derived neurotrophic factor [GDNF]) in hippocampus (HP), cerebral cortex, and striatum. Results: Δ9-THC-treated mice exhibited marked improvement in performance on the Y-maze indicating that treatment with the phytocannabinoid could reverse the deficit in working memory caused by the CCI. Δ9-THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. Δ9-THC-treated mice, compared with vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in the cerebral cortex, striatum, and HP. Levels of 2-AG were also increased in the Δ9-THC-treated mice. Conclusion: Administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke.”

https://pubmed.ncbi.nlm.nih.gov/34747647/

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

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ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Cannabidiol reduces lesion volume and restores vestibulomotor and cognitive function following moderately severe traumatic brain injury

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Experimental Neurology“Despite the high incidence of traumatic brain injury (TBI), there is no universal treatment to safely treat patients. Blunt brain injuries destroy primary neural tissue that results in impaired perfusion, excessive release of glutamate, inflammation, excitotoxicity, and progressive secondary neuronal cell death.

We hypothesized that administration of cannabidiol (CBD) directly to a brain contusion site, will optimize delivery to the injured tissue which will reduce local neural excitation and inflammation to spare neural tissue and improve neurological outcome following TBI.

CBD was infused into a gelfoam matrix forming an implant (CBDi), then applied over the dura at the contusion site as well as delivered systemically by injection (CBD.IP). Post-injury administration of CBDi+IP greatly reduced defecation scores, lesion volume, the loss of neurons in the ipsilateral hippocampus, the number of injured neurons of the contralateral hippocampus, and reversed TBI-induced glial fibrillary acidic protein (GFAP) upregulation which was superior to either CBD.IP or CBDi treatment alone.

Vestibulomotor performance on the beam-balance test was restored by 12 days post-TBI and sustained through 28 days. CBDi+IP treated rats exhibited preinjury levels of spontaneous alternation on the spontaneous alternation T-maze. In the object recognition test, they had greater mobility and exploration of novel objects compared to contusion or implant alone consistent with reduced anxiety and restored cognitive function.

These results suggest that dual therapy by targeting the site of injury internally with a CBD-infused medical carrier followed by systemic supplementation may offer a more effective countermeasure than systemic or implant treatment alone for the deleterious effects of penetrating head wounds.”

https://pubmed.ncbi.nlm.nih.gov/34428457/

“CBD improved vestibulomotor function and learning and memory cognitive performance post-TBI. Local delivery at the contusion site and systemic injection of CBD reduced TBI-induced lesion volume. Dual treatment, direct and systemic CBD, is superior to single treatment.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488621002521?via%3Dihub

http://www.thctotalhealthcare.com/category/brain-trauma/

Recovery from Traumatic Brain Injury Following Treatment with Δ9-Tetrahydrocannabinol Is Associated with Increased Expression of Granulocyte-Colony Stimulating Factor and Other Neurotrophic Factors

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View details for Cannabis and Cannabinoid Research cover image“The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) is well known to stimulate proliferation of blood stem/progenitor cells of the leukocyte lineage, but is also recognized as a neurotrophic factor involved in brain self-repair processes. G-CSF administration has been shown to promote recovery from experimental models of traumatic brain injury (TBI) and to modulate components of the endocannabinoid system (eCS). Conversely, Δ9-tetrahydrocannabinol (Δ9THC) treatment of normal mice has been shown to increase blood levels of G-CSF in the periphery. 

Hypothesis: Administration of the phytocannabinoid Δ9THC will enhance brain repair following controlled cortical impact (CCI) by upregulating G-CSF and other neurotrophic factors (brain-derived neurotrophic factor [BDNF] and glial-derived neurotrophic factor [GDNF]) in brain regions. 

Materials and Methods: C57BL/6J mice underwent CCI and were treated for 3 days with THC 3 mg/kg intraperitoneally. Motor function on a rotarod was recorded at baseline and 3, 7, and 14 days after CCI. Groups of mice were euthanized at 7 and 14 days. G-CSF, BDNF, and GDNF expression were measured at 7 and 14 days in cerebral cortex, striatum, and hippocampus on the side of the trauma. 

Results: Δ9THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. These mice, compared to vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in cerebral cortex, striatum, and hippocampus. 

Conclusion: Administration of the phytocannabinoid Δ9THC promotes significant recovery from TBI and is associated with upregulation of brain G-CSF, BDNF, and GDNF, neurotrophic factors previously shown to mediate brain self-repair following TBI and stroke.”

https://pubmed.ncbi.nlm.nih.gov/33998887/

https://www.liebertpub.com/doi/10.1089/can.2020.0119

Use of Medical Cannabis to Treat Traumatic Brain Injury

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View details for Journal of Neurotrauma cover image“There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury (TBI). With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option.

Preclinical TBI research suggests cannabinoids have neuroprotective and psychotherapeutic properties.

Our review identified a paucity of high-quality studies examining the beneficial and adverse effects of medical cannabis on traumatic brain injury, with only a single Phase III randomized control trial. However, observational studies demonstrate that TBI patients are using medical and recreational cannabis to treat their symptoms, highlighting inconsistencies between public policy, perception of potential efficacy, and the dearth of empirical evidence.

We conclude that randomized controlled trials and prospective studies with appropriate control groups are necessary to fully understand the efficacy and potential adverse effects of medical cannabis for TBI.”

https://pubmed.ncbi.nlm.nih.gov/33256496/

https://www.liebertpub.com/doi/10.1089/neu.2020.7148

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats

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 Issue Cover“The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity.

Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity.

Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries.

We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit.

Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex.

There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.”

https://pubmed.ncbi.nlm.nih.gov/32954298/

 “Overall, this study suggests that THC has potential therapeutic efficacy for the treatment of RmTBI-induced symptomology but requires additional examination.”

https://academic.oup.com/braincomms/article/2/1/fcaa042/5819138

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation-Evidence from In Vivo Studies

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jcm-logo“Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies.

In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments.

The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood-brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins.

In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.”

https://pubmed.ncbi.nlm.nih.gov/32726998/

https://www.mdpi.com/2077-0383/9/8/2395