The investigation of phytocannabinoids on TBI pathology not only holds topical relevance. Neuroprotective effects of CBD in hypoxic–ischemic brain damage model involve . models of brain trauma, supports the role of cannabinoids and their (GBM) is the most frequent class of malignant primary brain tumors. Here, we focus on a specific class of plant-metabolites, the (phyto) cannabinoids, and their effects in curing brain trauma.
Brain Traumatic Injury Primary and Phytocannabinoids
CB1 and CB2 receptors can also co-exist in a variety of concentrations in the same locations. Manipulations of endocannabinoid degradative enzymes, CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating numerous processes associated with neurodegenerative diseases, cancer, epilepsy, and traumatic brain injury [ Table 1 ].
In addition, the ECS is known to influence neuroplasticity, apoptosis, excitotoxicity, neuroinflammation, and cerebrovascular breakdown associated with stroke and trauma. Phytocannabinoid compounds and extracts can come from both hemp and marijuana subspecies, including CBD. CB1 receptors have the highest densities on the outflow nuclei of the basal ganglia, substantia nigra pars reticulata SNr , and the internal and external segments of the globus pallidus a portion of the brain that regulates voluntary movement.
Very few CB1 receptors are found in the brainstem. These locations suggest CB1 receptor involvement in the modulation of memory, emotion, pain, and movement. In patient studies with chronic pain and neuropathic pain, the use of marijuana or cannabinoid extracts produced positive and improved symptoms. Activation of neuronal CB1 receptors results in inhibition of adenylyl cyclase and decreased neurotransmitter release through blockade of voltage-operated calcium channels.
These effects have led to the study of phytocannabinoids for the treatment of epilepsy. Several pharmaceutical companies are attempting to develop synthetic high-affinity CB1 antagonists and inverse agonists as therapeutic drugs for diabetes, metabolic syndrome, and drug dependence. Like CB1 receptors, endocannabinoid stimulation inhibits neurotransmission of CB2 receptors. A study of cultured microglial cells showed c-interferon and granulocyte macrophage-colony stimulating factor GM-CSF , known as inflammatory response activators of microglial cell, were accompanied by significant CB2 receptor upregulation.
This increased expression was concomitant with the formation of amyloid-beta plaques, suggesting a potential utility for CB2 PET tracers as a diagnostic modality for detecting the onset of neuroinflammation. Specific cellular targets include neurons, endothelial cells, oligodendrocytes and microglial cells [ 12 , 78 , 92 , ]. Molecular targets of CBD, including cannabinoid and noncannabinoid receptors, enzymes, transporters, and cellular uptake proteins, help to explain CBD's low-binding affinity to both CB1 and CB2 cannabinoid receptors.
CBD appears to stimulate synaptic plasticity and facilitates neurogenesis that may explain its positive effects on attenuating psychotic, anxiety, and depressive behaviors. The mechanisms underlying these effects involve multiple cellular targets to elevate brain-derived neurotropic factor BDNF levels, reduce microglia activation, and decrease levels of proinflammatory mediators.
Ingested and absorbed CBD is rapidly distributed, and due to its lipophilic nature can easily pass the blood—brain barrier. The terminal half-life of CBD is about 9 h and is preferentially excreted in the urine as its free and glucuronide form. Research on the ECS is fervently ongoing with wide-ranging discoveries. The roles of endogenous cannabinoid, phytocannabinoids, and synthetic pharmacological agents acting on the various elements of the ECS have a potential to affect a wide range of pathologies, including food intake disorders, chronic pain, emesis, insomnia, glaucoma, gliomas, involuntary motor disorders, stroke, and psychiatric conditions such as depression, autism, and schizophrenia.
CBD research in animal models and humans has shown numerous therapeutic properties for brain function and protection, both by its effect on the ECS directly and by influencing endogenous cannabinoids.
Broadly, CBD has demonstrated anxiolytic, antidepressant, neuroprotective antiinflammatory, and immunomodulatory benefits. CBD decreases the production of inflammatory cytokines, influences microglial cells to return to a ramified state, preserves cerebral circulation during ischemic events, and reduces vascular changes and neuroinflammation.
CBD increases brain adenosine levels by reducing adenosine reuptake. Increased adenosine is associated with neuroprotection and decreased inflammation after brain trauma. These effects have been ascribed to inhibition of glutamate transmission, reduction of calcium influx, reduced microglial activation, and subsequent inhibition of noxious cascades, such as tumor necrosis factor-alpha generation and oxidative stress.
This can contribute to the pharmacological action to reduce nausea. Mechanisms include modulation of excitatory glutamatergic transmissions and synaptic plasticity, modulation of immune responses, the release of antiinflammatory mediators, modulation of excitability of N -methyl-D-aspartate receptors and its effect on gap junctions, calcium, and antioxidants.
Neurodegenerative diseases include a large group of conditions associated with progressive neuronal loss leading to a variety of clinical manifestations. Histomorphological changes can include gliosis and proliferation of microglia along with aggregates of misfolded or aberrant proteins. In addition, a wide range of non-ECS receptors can be influenced by both endogenous and phytocannabinoids.
AD is characterized by enhanced beta-amyloid peptide deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective against excitotoxicity in vitro and in patients with acute brain damage. In human AD patients, cellular studies of senile plaques have shown expression of cannabinoid receptors CB1 and CB2, together with markers of microglial activation.
Control CB1-positive neurons, however, are in greater numbers compared to AD areas of microglial activation. AD brains also have markedly decreased G-protein receptor coupling and CB1 receptor protein expression. Activated microglia cluster at senile plaques is generally believed to be responsible for the ongoing inflammatory process in the disease. In addition, AD-induced microglial activation and loss of neurons was inhibited.
AD-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor release, is blunted by cannabinoid compounds. CBD is effective in an experimental model of Parkinsonism 6-hydroxydopamine-lesioned rats by acting through antioxidant mechanisms independently of cannabinoid receptors. In rats lesioned with 3-nitropropionic acid, a toxin inhibitor of the mitochondrial citric acid cycle resulting in a progressive locomotor deterioration resembling that of HD patients, CBD reduces rat striatal atrophy in a manner independent of the activation of cannabinoid adenosine A2A receptors.
Activation of PPAR, along with CB1 and CB2, mediates numerous analgesic, neuroprotective, neuronal function modulation, antiinflammatory, metabolic, antitumor, gastrointestinal, and cardiovascular effects, both in and outside the ECS. The serotonin receptors have been implicated in the therapeutic effects of CBD.
In a rat model, CBD was observed to stimulate hippocampal neurogenesis. Neuroprotective effects of CBD in hypoxic—ischemic brain damage model involve adenosine A2 receptors. CBD activation of adenosine receptors can enhance adenosine signaling to mediate antiinflammatory and immunosuppressive effects. MS is an autoimmune disease that promotes demyelination of neurons and subsequent aberrant neuronal firing that contributes to spasticity and neuropathic pain.
The pathologic changes of MS include neuroinflammation, excitotoxicity, demyelination, and neurodegeneration. These pathological features share similarities with other neurodegenerative conditions, including AD and cerebral ischemia. The combination of antiinflammatory, oligoprotective, and neuroprotective compounds that target the ECS may offer symptomatic and therapeutic treatment of MS. The use of cannabis-based medicine for the treatment of MS has a long history and its interaction with the ECS shares many of the same pathways of other neurodegenerative conditions.
In , the American Academy of Neurology AAN published a review article of 34 studies investigating the use of medical marijuana as extracts, whole plants and synthetic phytocannabinoids for possible neurological clinical benefits. They found strong support for symptoms of spasticity and spasticity-related pain, excluding neuropathic pain in the research using oral cannabis extracts.
They reported inconclusive support for symptoms of urinary dysfunction, tremor, and dyskinesia. This study was subsequently used to form a consensus statement for their society. In the article they concluded their results based on the strength of the reported research [ Table 3 ]. Conclusions from Subcommittee of the American Academy of Neurology AAN systematic review on medical marijuana in neurologic diseases published in [ 66 ].
MS animal models using autoimmune encephalomyelitis EAE have been used that demonstrate demyelination, neuroinflammation, and neurological dysfunction associated with infiltration of immune cells into the CNS consistent with the human disease.
Upregulation of endocannabinoid tone protects neurons from excitotoxicity in parallel with a therapeutic effect in a mouse model of MS. In a week trial with a tolerated dose of 9-THC, subjects had reduced urinary incontinence, and a month follow-up demonstrated an antispasticity effect. CBD acts specifically to enhance adenosine signaling which increases extracellular adenosine, not AG Neuroprotective effects of CBD in hypoxic—ischemic brain damage also involve adenosine A2 receptors.
Specifically, CBD diminishes inflammation in acute models of injury and in a viral model of MS through adenosine A2 receptors. OPCs are highly vulnerable to inflammation and oxidative stress. Inflammation contributes to demyelinating diseases such as MS. Synthetic cannabinoids studies have shown they can protect OPCs possibly by controlling endoplasmic reticulum ER stress response that modulates the response to inflammatory stimuli.
It is an oral-mucosal spray containing a 1: The ability to modify pain may be attributed to a CB receptor-mediated regulation of supraspinal GABAergic and glutamatergic neurons. The results of these studies were cited in the AAN review. A meta-analysis in reported that CB receptor-based medications were superior to placebo in the treatment of MS-related neuropathic pain. Overall, the analgesic response to cannabinoids was generally retained over time, at least for the 6—10 weeks follow-up period.
CBD is recognized as a nonpsychoactive phytocannabinoid. Both human observational and animal studies, however, have demonstrated a broad range of therapeutic effects for several neuropsychiatric disorders. CBD has positive effects on attenuating psychotic, anxiety, and depressive-like behaviors. The mechanisms appear to be related to the CBD's benefit to provide enhanced neuroprotection and inhibition of excessive neuroinflammatory responses in neurodegenerative diseases and conditions.
Common features involving neuroprotective mechanisms influenced by CBD—oxidative stress, immune mediators, and neurotrophic factors—are also important in conditions such as posttraumatic stress disorder PTSD , postconcussion syndrome, depression, and anxiety.
Many studies confirm that the function of the ECS is markedly increased in response to pathogenic events like trauma. This fact, as well as numerous studies on experimental models of brain trauma, supports the role of cannabinoids and their interactions with CB1 and CB2 as part of the brain's compensatory and repair mechanisms following injury.
Animal studies indicate that posthead injury administration of exogenous CBD reduces short-term brain damage by improving brain metabolic activity, reducing cerebral hemodynamic impairment, and decreasing brain edema and seizures. These benefits are believed to be due to CBD's ability to increase anandamide. Treatment with CBD may also decrease the intensity and impact of symptoms commonly associated with PTSD, including chronic anxiety in stressful environments. In human studies, subjects introduced to fearful contexts exhibited decreased posttest anxiety when treated with CBD.
In rodent models, CBD effectively blocked the formation of fearful memories. Rat trials also show CBD's potential in fear memory extinction, demonstrated through a significant decrease in freezing time when re-exposed to an anxiety-inducing situation. Antidepressants, used for the treatment of depression and some anxiety disorders, also possess numerous neuroprotective properties, such as preventing the formation of amyloid plaques, elevation of BDNF levels, reduction of microglia activation, and decreased levels of proinflammatory mediators.
In rat models of neurobehavioral disorders, CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans.
A double-blind, randomized clinical trial with CBD reported a significant clinical improvement similar to the antipsychotic amisulpride, but with less side effects. Human imaging studies have demonstrated CBD affects brain areas involved in the neurobiology of psychiatric disorders.
A study has showed that a single dose of CBD, administered orally in healthy volunteers, alters the resting activity in limbic and paralimbic brain areas while decreasing subjective anxiety associated with the scanning procedure. In healthy volunteers treated with CBD and submitted to a presentation of fearful faces, there was a decrease of the amygdala and anterior and posterior cingulate cortex activities and a disruption in the amygdala—anterior cingulated cortex connectivity.
Interestingly, THC, administered prior to a traumatic insult in human case studies and animal models has had measurable neuroprotective effects. In general, conditions associated with chronic stress appear to be positively responsive to phytocannabinoids.
Studies in rat models reported that cannabinoids prevented the effects of acute stress on learning and memory and improved neuroplasticity, behavioral, and neuroendocrine measures of anxiety and depression. Cancer is a disease characterized by uncontrolled division of cells and their ability to spread. Novel anticancer agents are often tested for their ability to induce apoptosis and maintain steady-state cell population.
In the early s, phytocannabinoids were shown to inhibit tumor growth and prolong the life of mice with lung adenocarcinoma. Later studies have demonstrated cannabinoids inhibited tumor cell growth and induced apoptosis by modulating different cell signaling pathways in gliomas, lymphoma, prostate, breast, skin, and pancreatic cancer cells as well. Glioblastoma multiforme GBM is the most frequent class of malignant primary brain tumors. CBD has also been shown to reduce the growth of different types of tumor xenografts including gliomas.
The mechanism of action of CBD is thought to be increased production of ROS in glioma cells, thereby inducing cytotoxicity or apoptosis and autophagy. CBD also reduces angiogenesis through actions on both tumor and endothelial cells. Median survival was greater than days compared with days in the placebo group. Reports of cannabis use in the treatment of epilepsy appear as far back as BC. Scientific reports appear in from neurologists using Indian hemp to treat epilepsy with dramatic success.
CBD, however, produces antiepileptiform and anticonvulsant effects in both in vitro and in vivo models. More recently in , Cunha et al. Each patient received — mg daily of CBD or placebo along with antiepileptic drugs for up to 4 months. In the placebo group 1 of 8 responded with fewer seizures. These all suggest that CBD, the nonpsychoactive compound of cannabis, potentially can be helpful for controlling medication refractory seizures.
As with most cannabinoid research to date, conducting studies can be difficult due to limited legal access to medical grade marijuana and phytocannabinoid extracts. Hemp-derived CBD, however, has recently experienced less regulation and as a result research using CBD for refractory epilepsy has experienced a resurgence. CBD's overall effect appears to result in reduction of neuronal hyperactivity in epilepsy.
Anandamide affects excitability in neuronal networks by activating the transient receptor potential TRP cation channel. Endogenous cannabinoids appear to affect the initiation, propagation, and spread of seizures. Studies have identified defects in the ECS in some patients with refractory seizure disorders, specifically having low levels of anandamide and reduced numbers of CB1 receptors in CSF and tissue biopsy.
Although this study exclusively looked for effects on seizure incidence, no evidence suggests that the antiseizure effects of CBD are limited to the treatment of this condition. Development of synthetic forms of CBD is also in progress to treat seizure and other disorders responsive to the phytocannabinoid CBD.
A comprehensive safety and side effect review of CBD in on both animal and human studies described an excellent safety profile of CBD in humans at a wide variety of doses. CBD does have interactions with common hepatic drug -metabolizing enzymes, belonging to the cytochrome P family.
Therefore, interactions with drug transporters and interactions with drugs must be considered. In contrast to THC, CBD does not alter heart rate, blood pressure, or body temperature, does not induce catalepsy, nor alter psychomotor or psychological functions.
The AAN review of 34 articles on MS using cannabinoids of various forms noted several adverse effects. Reported symptoms included nausea, increased weakness, behavioral or mood changes or both , suicidal ideation or hallucinations, dizziness or vasovagal symptoms or both , fatigue, and feelings of intoxication. Psychosis, dysphoria, and anxiety were associated with higher concentrations of THC. However, no direct fatalities or overdoses have been attributed to marijuana, even in recreational users of increasingly potent marijuana possibly due to lack of endocannabinoid receptors in the brainstem.
Like other cannabinoids, CBD produces bell-shaped dose—response curves and can act by different mechanisms according to its concentration or the simultaneous presence of other cannabinoid-ligands. Ultimately, prescribing medical marijuana either as a primary treatment or adjunctive therapy will require extreme care and knowledge about the patient's goals and expectations for treatment.
States that have allowed medical marijuana have generally required competency trainings and certification prior to prescribing. There are general screening questions that should be considered before recommending marijuana to a patient.
At minimum, these questions should include the following: Although these medications are often cited in human clinical research, their general use is limited based both on side effects and indication constraints.
Although federal and state laws are inconsistent about the legality of cannabis production, its increasingly documented health benefits make it once again relevant in medicine. Current research indicates the phytocannabinoids have a powerful therapeutic potential in a variety of ailments primarily through their interaction with the ECS. CBD is of particular interest due to its wide-ranging capabilities and lack of side effects in a variety of neurological conditions and diseases.
Because of the rapid legalization of medical marijuana by the majority of state legislatures in the U. Because of federal restrictions on human research in the U. This review of the neurological benefits of phytocannabinoids has demonstrated significant benefits for neuroprotection and disease reductions in a wide variety of neurological diseases and conditions in humans. The Authors report the following conflicts: National Center for Biotechnology Information , U.
Journal List Surg Neurol Int v. Published online Apr Author information Article notes Copyright and License information Disclaimer. Received Feb 5; Accepted Feb This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4. This article has been cited by other articles in PMC. Cannabidiol, deltatetrahydrocannabinol, endocannabinoid system, neurological disease, phytocannabinoids. Open in a separate window.
Cannabinoid receptors Phytocannabinoid compounds and extracts can come from both hemp and marijuana subspecies, including CBD. Activation of neuronal CB1 receptors Activation of neuronal CB1 receptors results in inhibition of adenylyl cyclase and decreased neurotransmitter release through blockade of voltage-operated calcium channels. Cultured microglial dells A study of cultured microglial cells showed c-interferon and granulocyte macrophage-colony stimulating factor GM-CSF , known as inflammatory response activators of microglial cell, were accompanied by significant CB2 receptor upregulation.
Research on the endocannabinoid system Research on the ECS is fervently ongoing with wide-ranging discoveries. Neuroprotective benefits of phytocannabinoids CBD research in animal models and humans has shown numerous therapeutic properties for brain function and protection, both by its effect on the ECS directly and by influencing endogenous cannabinoids.
Neurodegenerative diseases Overview Neurodegenerative diseases include a large group of conditions associated with progressive neuronal loss leading to a variety of clinical manifestations. Neuroprotection for AD AD is characterized by enhanced beta-amyloid peptide deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabidiol CBD is effective in an experimental model of Parkinsonism 6-hydroxydopamine-lesioned rats by acting through antioxidant mechanisms independently of cannabinoid receptors.
Multiple sclerosis CBD and deltaTHC MS is an autoimmune disease that promotes demyelination of neurons and subsequent aberrant neuronal firing that contributes to spasticity and neuropathic pain. Use of cannabis-based medicine for neurodegenerative conditions The use of cannabis-based medicine for the treatment of MS has a long history and its interaction with the ECS shares many of the same pathways of other neurodegenerative conditions.
American Academy of Neurology statement on medical marijuana In , the American Academy of Neurology AAN published a review article of 34 studies investigating the use of medical marijuana as extracts, whole plants and synthetic phytocannabinoids for possible neurological clinical benefits. MS animal models utilizing deltaTHC MS animal models using autoimmune encephalomyelitis EAE have been used that demonstrate demyelination, neuroinflammation, and neurological dysfunction associated with infiltration of immune cells into the CNS consistent with the human disease.
Neuropsychiatric and brain trauma Cannabidiol CBD is recognized as a nonpsychoactive phytocannabinoid. Antidepressant and neuroprotective properties Antidepressants, used for the treatment of depression and some anxiety disorders, also possess numerous neuroprotective properties, such as preventing the formation of amyloid plaques, elevation of BDNF levels, reduction of microglia activation, and decreased levels of proinflammatory mediators.
Rat models; efficacy of CBD in neurobehavioral disorders In rat models of neurobehavioral disorders, CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans. Human imaging studies correlated with CBD Human imaging studies have demonstrated CBD affects brain areas involved in the neurobiology of psychiatric disorders.
Tetrahydrocannabinol Interestingly, THC, administered prior to a traumatic insult in human case studies and animal models has had measurable neuroprotective effects. Utility for glioblastoma multiforme Glioblastoma multiforme GBM is the most frequent class of malignant primary brain tumors.
CBD reduces growth different tumor xenografts CBD has also been shown to reduce the growth of different types of tumor xenografts including gliomas. Intractable epilepsy Cannabidiol Reports of cannabis use in the treatment of epilepsy appear as far back as BC. CBDs reduce neuronal hyperactivity in epilepsy CBD's overall effect appears to result in reduction of neuronal hyperactivity in epilepsy. Endogenous cannabinoids Endogenous cannabinoids appear to affect the initiation, propagation, and spread of seizures.
Safety A comprehensive safety and side effect review of CBD in on both animal and human studies described an excellent safety profile of CBD in humans at a wide variety of doses. The exploration of how anandamide may be exerting its protective effects of BBB integrity may yet yield further novel targets for the treatment of TBI. In cerebral circulation, CB 1 receptor activation produces vasodilation. Indeed, the CB 1 receptor antagonist rimonabant inhibited hypotension induced by endotoxin shock and hemorrhagic shock, as well as increasing survival Varga et al.
Though cannabinoids are yet to be explored in the context of TBI-induced changes in cerebral blood flow, CB 1 receptor antagonism may prove to be a potential target for the treatment of TBI-induced hypotension. The key biological idea that structure dictates function also holds true for the neurophysiology of TBI. The use of cannabinoids has thus far been linked to protection against several of the CNS structural changes associated with TBI, with 2-AG being the most frequently studied eCB in this area.
While a traumatic insult can result in the rapid onset of cerebral oedema, exogenously administered 2-AG protects against TBI-induced oedema Panikashvili et al. Changes in protein physiology have also been found to occur following TBI. These proteins are thought to accumulate from damaged axons and as a result of a disturbed balance between genesis and catabolism Johnson et al.
MAGL inhibition also decreases astrocyte activation Mayeux et al. These consistent protective effects of 2-AG across varied TBI-related structural pathologies point to its important role in maintaining cell structure and promoting remodeling. Protective roles played by anandamide in injury-induced structural changes are yet to be ascertained. Furthermore, eCBs may not be working alone to offer protection from TBI-induced structural impairments. These findings suggest that the regulatory activity of the eCB receptors in response to TBI may be mediated by endocrine as well as paracrine signaling mechanisms.
Traumatic brain injury is well described to increase CB 1 and CB 2 receptor expression, which includes disruption of diurnal rhythms of CB 1 receptor expression Martinez-Vargas et al. Post-injury treatment with a CB 1 receptor antagonist reduces CB 1 receptor expression at 6 weeks following injury Wang et al.
The exact CNS circuits involved in NPE have yet to be identified, though a sudden rise in intracranial pressure, rapid sympathetic surge, increased systemic vascular resistance and increase in hydrostatic pressure in the pulmonary vasculature, as well as release of pro-inflammatory mediators may all contribute to interstitial pulmonary oedema formation Brambrink and Dick, While at the present time there are no studies evaluating the contributions of, or protection by, the eCB system to NPE following TBI, this may prove an interesting area of future investigation.
Specifically, the lung possesses a basal tone of 2-AG Avraham et al. The heterogeneous clinical presentation of TBI pathology in populations of survivors is reminiscent of its cellular and molecular pathophysiology described above.
Most frequently investigated measures in the pre-clinical TBI literature include neurological motor, and learning and memory impairments, leaving a wide breadth of TBI clinical effects yet to be studied.
Once again, components of the eCB system may become active to compensate for TBI symptomology given what is currently known of its regulatory effects within these areas, two examples being pain, and anxiety and depression Corcoran et al. Learning and memory impairments are among the most frequently reported symptoms following TBI, and are slow to recover with deficiencies reported 10 years later Zec et al.
The eCB system has been shown to play a well-documented role in memory regulation reviewed in Mechoulam and Parker, , and as such its manipulation holds considerable promise to address such a profound consequence of TBI. The protective effects of 2-AG appear to be task specific, with ABHD6 inhibition showing learning and memory protection in a Y-maze task, but not a Morris water maze task. To date, only a Y-maze task has been used to evaluate the memory protective effects of FAAH inhibition, and this task-specific effect did not occur with a MAGL inhibitor.
Mice are a well-used pre-clinical model organism to study the memory effects of TBI; however, they are known to perform behavioral tasks more readily, and with less error, when the task does not rely on aversive motivation Stranahan, This attribute of mice may, in some part, contribute to the task-related differences seen between the Y-maze task which uses exploratory behaviors associated with novelty and the aversively motivated escape behavior necessary in the Morris water maze.
Moving forward, the use of behavioral tasks able to selectively assess such frontal lobe-type memory impairments might improve the translational capacity of eCB TBI pre-clinical assessments one such example being the Morris water maze Reversal Task, which evaluates cognitive flexibility. Traumatic brain injury-induced neurological motor impairments currently represent the most frequently studied behavioral outcome measure in the TBI-cannabinoid literature.
In clinical populations, neurological motor impairments seen as a result of TBI show spontaneous improvement over time, but one third of patients continue to experience neuromotor abnormalities 2 years after injury Walker and Pickett, A variety of eCB system manipulations have thus far been found to be protective against the neurological motor deficits associated with murine models of TBI. Both 2-AG and anandamide elevation provide protection against TBI-induced neurological motor deficits.
MAGL inhibitors Zhang et al. FAAH inhibition has produced mixed findings in neurological motor tests, such as beam-walk deficit protection Tchantchou et al. In support of anandamide being protective against TBI-induced motor deficits, exogenous anandamide has also produced improved NSS performance Martinez-Vargas et al.
The involvement of the CB 2 receptor is further supported by rotarod deficit protection from a CB 2 receptor agonist Amenta et al. The role of entourage effects has also been evaluated in the area of TBI-induced neurological motor impairments. Co-release of endogenous fatty acid derivatives can potentiate 2-AG signaling, termed an entourage effect Ben-Shabat et al.
Given FAAH is responsible for the degradation of various fatty acid amides in addition to anandamide Boger et al. Thus any inferences drawn about anandamide through the use of FAAH inhibition needs to consider contributions of non-cannabinoid fatty acid amides.
The signs of post-traumatic anxiety have been difficult to replicate in murine models of TBI Tucker et al. Also, as there is a limited number of studies evaluating eCBs in this area, no definitive conclusions can be made. Thus far, only FAAH inhibition has been explored to address post-traumatic anxiety, and was found to protect against TBI-induced increases in anxiety-like behavior in mice Tchantchou et al.
This protection in the zero maze was unaffected by either CB 1 or CB 2 receptor antagonists, suggesting that these receptors are dispensable. Modeling post-traumatic epilepsy is time consuming and faces other challenges such as a low percentage of animals that develop epilepsy Mazarati, , however, recent models that produce consistent replication of spontaneous seizure activity following a TBI are available Ping and Jin, Contrary to preclinical research demonstrating that the eCB system plays a protective roles against seizures Wallace et al.
This nascent body of data, suggests that eCB manipulations hold promise to treat injury-induced clinical symptoms outside of the more popular areas of learning and memory and neurological motor impairments. Although currently well over one hundred phytocannabinoids have been elucidated from the Cannabis sativa plant Elsohly et al. The investigation of phytocannabinoids on TBI pathology not only holds topical relevance, but also but also holds promise as potential treatment for TBI and other disorders.
However, clinical and pre-clinical findings provide evidence suggesting that the primary psychoactive constituent of Cannabis sativa , THC, is neuroprotective when administered prior to a traumatic insult.
In a 3 year retrospective study of patients who had sustained a TBI, urine toxicology screen results showed decreased mortality in individuals with a positive THC screen Nguyen et al. In two mouse models of CNS injury that yield cognitive deficits, pentylenetetrazole an excitotoxic agent and carbon monoxide induced hypoxic injury, prior administration of THC provided impairment protection Assaf et al.
Curiously, an extraordinarily a low dose of THC i. The authors explained this effect through the known biphasic effects of THC producing analgesia, acute hypothermia, and decreased locomotion at high doses 10 mg. Such low dose effects of THC have been found to potentiate calcium entry into cells in vitro Okada et al. Therefore, Assaf et al. Moreover, the molecular signaling cascades behind cardiac and cerebral ischaemia preconditioning include activation of ERK and Akt Dirnagl et al.
As such, individuals may experience very low plasma THC concentrations for prolonged periods after each application. This presumed prolonged exposure of THC due to its pharmacokinetics, as well as other potentially neuroprotective cannabinoids, such as CBD Perez et al. A finding of increased clinical relevance, is that post-conditioning when the mildly noxious stimulus is applied after the insult with low dose THC also produced cognitive sparing effects in mice Assaf et al.
These findings, however, remain controversial, and are yet to be replicated in animal models of TBI. The phytocannabinoid CBD, currently being investigated in clinical trials for its seizure reduction potential in Tuberous Sclerosis Complex Gw Research Ltd, , has known anti-inflammatory properties.
As such CBD may be a promising future avenue of investigation in the study of neuroinflammation in response to brain injury.
The eCB system, through release of its endogenous ligands or by changes in cannabinoid receptor constitutive activity, possesses promise in the treatment of diverse TBI pathology. An important step forward in understanding the role that the eCB system plays in TBI pathology includes not only the full characterization of ligands targeting cannabinoid receptors and eCB regulating enzymes, but also changes in cannabinoid receptors, eCB levels, and eCB regulating enzymes as a consequence of TBI.
So too do the plant-derived phytocannabinoids represent an understudied yet promising group of compounds given the neuroprotective results obtained from other types of CNS injury. In particular, CBD as well as other phytocannabinoids which do not bind cannabinoid receptors, represent promising molecules to treat TBI. To date, the only reported cannabinoid to be specifically evaluated for the treatment of TBI in patient populations is Dexanabinol, also known as HU Although HU has been described as a cannabinoid by virtue that it is an enantiomer of the potent synthetic cannabinoid agonist HU, it does not bind or activate cannabinoid receptors.
This therefore brings to light an important consideration of the classification of cannabinoids. One consistently overlooked area across the study of TBI is the evaluation of the central penetration of systemically administered drugs. Pharmacological treatments will need to be assessed for their ability to cross the BBB. Furthermore, given the often biphasic nature of cannabinoid drugs, it is critical to move away from single dose pharmacology to full dose-response assessments, which may yield an increased understanding of the mechanism and potential of cannabinoids to treat TBI.
Overall, the abundant and growing pre-clinical research suggests that the eCB system possesses many promising targets for new and existing drugs that may ameliorate diverse TBI pathology. LS performed the literature review and composed the article; AL contributed to the composition of the article.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This research was funded by a Ruth L. National Center for Biotechnology Information , U. Journal List Front Pharmacol v.
Published online Feb Schurman and Aron H. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology. Received Oct 15; Accepted Feb 2. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract The endogenous cannabinoid endocannabinoid system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors i.
Open in a separate window. Traumatic Brain Injury Pathology Traumatic brain injuries are heterogeneous in their etiology, clinical presentation, severity, and pathology. Table 1 Effect of cannabinoids on TBI-induced cellular and molecular pathophysiology. CNS Cell Death Traumatic brain injury-induced neuronal loss occurs almost immediately as necrotic cell death and continues for months following the initial insult via both necrotic and apoptotic cell death Raghupathi, Excitotoxicity Previous efforts to attenuate the effects of excitotoxicity following brain injury focused on NMDA receptor antagonists, presumably with the understanding that the induction of depressed NMDA receptor function would counteract TBI-induced excitotoxicity.
Neuroinflammation Hydrolytic enzymes of anandamide and 2-AG produce a shared metabolic product in the formation of free AA, the major substrate of the biosynthetic enzymes of pro-inflammatory eicosanoids Nomura et al. Cerebrovascular Breakdown The blood vessels which carry oxygen rich blood to the brain are lined by endothelial cells as well as astrocytes.
Treatment of Behavioral Deficits of TBI The heterogeneous clinical presentation of TBI pathology in populations of survivors is reminiscent of its cellular and molecular pathophysiology described above. Table 2 Effect of cannabinoids on TBI-induced behavioral impairments. Learning and Memory Learning and memory impairments are among the most frequently reported symptoms following TBI, and are slow to recover with deficiencies reported 10 years later Zec et al.
Neurological Motor Traumatic brain injury-induced neurological motor impairments currently represent the most frequently studied behavioral outcome measure in the TBI-cannabinoid literature. Primary Phytocannabinoids and Traumatic Brain Injury Although currently well over one hundred phytocannabinoids have been elucidated from the Cannabis sativa plant Elsohly et al.
Concluding Remarks and Future Directions The eCB system, through release of its endogenous ligands or by changes in cannabinoid receptor constitutive activity, possesses promise in the treatment of diverse TBI pathology. Author Contributions LS performed the literature review and composed the article; AL contributed to the composition of the article. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Pathogenesis, clinical picture and therapy. Guidelines for the surgical management of traumatic brain injury. Factors affecting excitatory amino acid release following severe human head injury. CB2 receptors in the brain: Inhibition of an equilibrative nucleoside transporter by cannabidiol: Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.
Blood-brain barrier pathophysiology in traumatic brain injury. N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia.
The epidemiology of traumatic brain injury. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: Monoacylglycerol lipase MAGL inhibition attenuates acute lung injury in mice. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Production and physiological actions of anandamide in the vasculature of the rat kidney. Determination and characterization of a cannabinoid receptor in rat brain. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Targeting the endocannabinoid system: To enhance or reduce? Brain monoglyceride lipase participating in endocannabinoid inactivation.
Ischemic tolerance and endogenous neuroprotection. A new perspective on cannabinoid signalling: Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.
The neurophysiology of brain injury. Phytocannabinoids beyond the Cannabis plant — do they exist? Cerebral preconditioning and ischaemic tolerance. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. A2A receptors in inflammation and injury: Hemopressin is an inverse agonist of CB1 cannabinoid receptors.
Characterization and localization of cannabinoid receptors in rat brain: Voltage-gated sodium NaV channel blockade by plant cannabinoids does not confer anticonvulsant effects per se.
Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat. Endocannabinoids and vascular function 1.
Endocannabinoids modulate human blood-brain barrier permeability in vitro. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. TRPV1 activation results in disruption of the blood-brain barrier in the rat.
Endocannabinoid degradation inhibition improves neurobehavioral function, blood-brain barrier integrity, and neuroinflammation following mild traumatic brain injury. Cerebral blood flow as a predictor of outcome following traumatic brain injury. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord.
Dexanabinol HU in the treatment of severe closed head injury: Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury. The palmitoylethanolamide and oleamide enigmas: Are these two fatty acid amides cannabimimetic? The epidemiology and impact of traumatic brain injury: Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo.
Estradiol decreases cortical reactive astrogliosis after brain injury by a mechanism involving cannabinoid receptors. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. Efficacy and safety of dexanabinol in severe traumatic brain injury: Mechanisms of CB1 receptor signaling: CB1 cannabinoid receptors and on-demand defense. Does the neuroprotective role of anandamide display diurnal variations?
Inhibition of endocannabinoid degradation improves outcomes from mild traumatic brain injury: Is posttraumatic epilepsy the best model of posttraumatic epilepsy?
Review of the neurological benefits of phytocannabinoids
Traumatic brain injury (TBI) is one of the leading causes of death both acute and potentially lethal injuries, involving a primary ischemic insult that Plant cannabinoids such as THC and CBD mimic and augment the activity. potential for use of phytocannabinoids to treat pain, migraine and concussion. First draft nonmilitary patients with concussion or traumatic brain injury [1,6,9]. Diagnostic .. 9-THC is the primary psychoactive constituent. Cannabinoids and Acute Brain Damage: Stroke and Brain Trauma . The existence of a lapse between primary and secondary energetic.