Category Archives: 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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Δ9-THC promoted recovery after traumatic brain injury in mice. Animals treated with THC for three days after a controlled cortical impact performed better on motor testing and returned to normal motor performance within two weeks.

The recovery was accompanied by increased expression of G-CSF, BDNF, and GDNF in brain regions including the cortex, striatum, and hippocampus. These neurotrophic factors are involved in neuronal survival, brain repair, and recovery after injury.

The findings suggest that THC may support recovery after traumatic brain injury by increasing the brain’s own repair-related signaling. In this study, the effect went beyond symptom relief and was associated with biological changes tied to neuroprotection and regeneration.

“Introduction: 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://journals.sagepub.com/doi/10.1089/can.2020.0119

Need this THC study explained? thcXplained.com

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

Cannabidiol alleviates hemorrhagic shock-induced neural apoptosis in rats by inducing autophagy through activation of the PI3K/AKT pathway.

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Publication cover image“Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia-induced brain injury. However, the protective effect of CBD against mitochondrial-dependent apoptosis in hemorrhagic shock (HS)-induced brain injury has not been studied.

In the present study, we observed the protective effects of CBD against neural mitochondrial-dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin-1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro-apoptosis ratio and NF-κB signaling activation, and upregulation of BCL2 in the cerebral cortex.

Such protective effects were reversed by 3-Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD-induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD’s regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1.

Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS-mediated mitochondrial-dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/32215966

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12557

“Hemorrhagic shock occurs when the body begins to shut down due to large amounts of blood loss.” https://www.healthline.com/health/hemorrhagic-shock

Cannabidiol in sport : ergogenic or else?

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Pharmacological Research“In the sports domain, cannabis is prohibited by the World Anti-Doping Agency (WADA) across all sports in competition since 2004. The few studies on physical exercise and cannabis focused on the main compound i.e. Δ9-tetrahydrocannabinol. Cannabidiol (CBD) is another well-known phytocannabinoid present in dried or heated preparations of cannabis. Unlike Δ9-tetrahydrocannabinol, CBD is non-intoxicating but exhibits pharmacological properties that are interesting for medical use.

The worldwide regulatory status of CBD is complex and this compound is still a controlled substance in many countries. Interestingly, however, the World Anti-Doping Agency removed CBD from the list of prohibited substances – in or out of competition – since 2018. This recent decision by the WADA leaves the door open for CBD use by athletes.

In the present opinion article we wish to expose the different CBD properties discovered in preclinical studies that could be further tested in the sport domain to ascertain its utility. Preclinical studies suggest that CBD could be useful to athletes due to its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.”

https://www.ncbi.nlm.nih.gov/pubmed/32205233

“Athletes could benefit from CBD to manage pain, inflammation and the swelling processes associated with injury. CBD could be useful to manage anxiety, fear memory process, sleep and sleepiness in athletes. CBD could be interesting for the management of mild traumatic brain injury and chronic traumatic encephalopathy.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661819326143?via%3Dihub

Matched pilot study examining cannabis-based dronabinol for acute pain following traumatic injury.

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BMJ Journals“To determine whether adjunctive dronabinol, a licensed form of delta-9-tetrahydrocannabinol, reduces opioid consumption when used off-label for managing acute pain following traumatic injury.

CONCLUSIONS:

The results of this study suggest adjunctive dronabinol reduces opioid consumption following traumatic injury.

The opioid-sparing effect of dronabinol may be greater in patients who are marijuana users.”

https://www.ncbi.nlm.nih.gov/pubmed/32154376

https://tsaco.bmj.com/content/5/1/e000391

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

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 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z

Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.

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 Scientific Reports“Brain trauma was clinically associated with increased osteogenesis in the appendicular skeleton. We showed previously in C57BL/6J mice that mild traumatic brain injury (mTBI) transiently induced bone formation in the femur via the cannabinoid-1 (CB1) receptor. Here, we subjected ICR mice to mTBI and examined the bone response in the skull using microCT. We also measured mast cell degranulation (MCD)72 h post-injury. Finally, we measured brain and calvarial endocannabinoids levels post-mTBI. mTBI led to decreased bone porosity on the contralateral (untouched) side. This effect was apparent both in young and mature mice. Administration of rimonabant (CB1 inverse agonist) completely abrogated the effect of mTBI on calvarial porosity and significantly reduced MCD, compared with vehicle-treated controls. We also found that mTBI resulted in elevated levels of anandamide, but not 2-arachidonoylglycerol, in the contralateral calvarial bone, whereas brain levels remained unchanged. In C57BL/6J CB1 knockout mice, mTBI did not reduce porosity but in general the porosity was significantly lower than in WT controls. Our findings suggest that mTBI induces a strain-specific CB1-dependent bone anabolic response in the skull, probably mediated by anandamide, but seemingly unrelated to inflammation. The endocannabinoid system is therefore a plausible target in management of bone response following head trauma.”

https://www.ncbi.nlm.nih.gov/pubmed/31700010

https://www.nature.com/articles/s41598-019-51720-w

Cannabis, alcohol and cigarette use during the acute post-concussion period.

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Publication Cover

“Objective: To document the prevalence of acute post-concussion cannabis, alcohol and cigarette use and their association with clinical recovery and symptom burden.

Results: A total of 307 acute concussions with a mean age of 33.7 years (SD, 13.0) were included. Acute post-concussion cannabis, alcohol and cigarette use were identified in 43 (14.0%), 125 (40.7%) and 61 (19.9%) individuals. Acute cannabis, alcohol and cigarette use were not associated with recovery to cognitive (p > .05) or physical activity (p > .05). Acute cigarette use was associated with a higher unadjusted symptom severity score at week1 (p = .003). Acute cannabis use was associated with lower symptom severity scores at week-3 (p = .061) and week-4 (p = .029).

Conclusion: In conclusion, cannabis, alcohol and cigarette use were prevalent in the acute period post-concussion; however, were not observed to impact recovery within the first 4 weeks post-injury. Amongst unrecovered individuals, acute cannabis use was associated with lower symptom burden, while cigarette use was associated with greater initial symptom burden.”

 https://www.ncbi.nlm.nih.gov/pubmed/31621424
https://www.tandfonline.com/doi/abs/10.1080/02699052.2019.1679885?journalCode=ibij20