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Traumatic brain injury (TBI) is one of the leading causes of death worldwide in individuals under the age of 45. Triggered by concussions from car accidents, falls, violent contact sports, explosives or by gunshot and stab wounds, TBI affects 1.7 million Americans annually. It is the most commonly identified cause of epilepsy among adults.

The social and economic costs of TBI are considerable given that many who survive severe head injuries suffer permanent behavioral and neurological impairment that adversely impacts learning and memory and often requires long term rehabilitation. An estimated 4 million to 6 million Americans are on disability because of TBI. Even so-called mild cases of TBI can result in post-traumatic seizures, refractory cognitive deficits, and lower life expectancy.

Treatment modalities for TBI are limited with few satisfactory pharmaceutical options available. Surgical intervention, which entails the removal of parts of the skull to reduce intracranial pressure, is an emergency, life-saving measure, and the aftermath can be gruesome.

But hope is on the horizon, thanks in part to U.S. government-sponsored scientific research – and to extensive anecdotal accounts from medical marijuana patients – which highlight the potential of cannabinoid-based therapies for TBI.

The patent

In 1998, the Proceedings of the National Academy of Sciences published a groundbreaking report on the neuroprotective properties of cannabidiol (CBD) and tetrahydrocannabinol (THC), two major components of marijuana. Co-authored by a team of researchers (AJ Hampson, M Grimaldi, D Wink and Nobel laureate J Axelrod) at the National Institutes of Mental Health, this preclinical study on rats would form the basis of a U.S. government-held patent on “Cannabinoids as antioxidants and neuroprotectants.”

The patent indicates that CBD and THC were found “to have particular application as neuroprotectants … in limiting neurological damage following ischemic insults, such as stroke or trauma.” These plant cannabinoids were also deemed useful for treating other neurodegenerative conditions, “such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.”

Whereas TBI results from an external blow to the skull, a stroke is caused internally by an arterial blockage or rupture. But TBI and stroke share many of the same pathological features and aberrant molecular mechanisms.

TBI and stroke are both acute and potentially lethal injuries, involving a primary ischemic insult that interrupts cerebral blood flow and destroys brain tissue. This is followed by a secondary injury cascade that, if unchecked, can ricochet for several weeks or months, resulting in more brain damage, motor impairment and other adverse “downstream” effects, such as poor concentration, irritability, and sleep problems.

Whether the cause is an occluded blood vessel or blunt external force, the initial trauma triggers a complex sequence of molecular events characterized by the massive release of glutamate (an excitatory neurotransmitter) and the overproduction of reactive oxygen species (free radicals) and other inflammatory compounds. Excessive glutamate and oxidative stress, in turn, lead to microvascular injury, blood-brain barrier breakdown, swollen brain tissue, mitochondrial dysfunction, calcium ion imbalance, neurotoxicity and cell death. The secondary injury cascade is associated with the development of many of the neurological deficits observed after a TBI or a stroke.

Cannabinoids to the rescue

A 2014 article in American Surgeon examined how marijuana use affected people who suffered a traumatic brain injury. “A positive THC screen is associated with decreased mortality in adult patients sustaining TBI” the study concluded.

According to this noteworthy report by UCLA Medical Center scientists, TBI-afflicted individuals who consume marijuana are less likely to die and more likely to live longer than TBI patients who abstain.

How does cannabis, and THC, in particular, confer neuroprotective effects?

Plant cannabinoids such as THC and CBD mimic and augment the activity of endogenous cannabinoids that all mammals produce internally. Endogenous cannabinoids are part of the endocannabinoid system (ECS). The ECS regulates many physiological processes that are relevant to TBI, such as cerebral blood flow, inflammation, and neuroplasticity.

A 2011 article in the British Journal of Pharmacology describes the ECS as “a self-protective mechanism” that kicks into high gear in response to a stroke or TBI. Co-authored by Israeli scientist Raphael Mechoulam, the article notes that endocannabinoid levels in the brain increase significantly during and immediately after a TBI. These endogenous compounds activate cannabinoid receptors, known as CB1 and CB2, which protect against TBI-induced neurological and motor deficits.1

THC activates the same receptors – with similar health-positive effects.

Of knockout mice and men

CB1 receptors are concentrated in the mammalian brain and central nervous system. Preclinical research involving animal models of TBI and stroke has shown that heightened CB1 receptor transmission can limit harmful excitoxicity by inhibiting glutamate release. CB1 receptor activation also dilates blood vessels, thereby enhancing cerebral blood flow (and oxygen and nutrient supply to the brain).

But these beneficial physiological changes were not evident in genetically-engineered “knock out” mice that lack CB1 receptors. Without these crucial receptors, an animal is less able to benefit from the neuroprotective properties of endogenous cannabinoids and plant cannabinoids.

In 2002, the Journal of Neuroscience reported that the impact of induced cerebral ischemia is much more severe in CB1 knockout mice than in “wild type” mice with cannabinoid receptors. The absence of CB1 was shown to exacerbate TBI-related brain damage and cognitive deficits, indicating that cannabinoid receptors play an important role in neuroprotection.

The CB1 paradox

By manipulating cannabinoid receptors and other components of the endocannabinoid system with synthetic and plant-derived compounds, medical scientists have been able to reduce brain injury in animal experiments.

But CB1 proved to be a tricky target.

In 2013, the International Journal of Molecular Science reported on how TBI is affected by diurnal variations of the endocannabinoid system. It turns out that the recovery and survival rate of concussed lab rats is significantly higher if a TBI occurs at 1 am, when CB1 receptors are least robust, as compared to 1 pm, when CB1 receptor expression peaks.

This finding was somewhat perplexing given the protective function of the endocannabinoid system against brain trauma.

The ECS is a complex, front-line mediator of acute stress, and the pivotal role of the CB1 receptor is contingent on several variables, including time of day, the phase of the ischemic injury, and endocannabinoid concentrations in the brain. Small and large amounts of cannabinoid compounds produce opposite effects.

When excess glutamate is released, CB1 activity increases to reduce excitotoxic neurotransmission. But CB1 also regulates apoptosis (cell death), acting as a switch between cell survival and cell death. Extreme CB1 activation could trigger cell death even while it reduces glutamate release. It’s possible that a weak CB1 antagonist (that partially blocks CB1 transmission) might limit apoptosis while still reducing glutamate excitotoxicity.2

CB2 and neurogenesis

After an initial infatuation with CB1, medical scientists shifted their attention to the CB2 receptor as a drug development target for treating TBI. The CB2 receptor modulates immune function and inflammation. It is expressed primarily in immune cells, metabolic tissue, and the peripheral nervous system.

CB2 receptor expression, unlike CB1, does not vary according to the hour of the day. But during and after severe head trauma, CB2 receptor expression is dramatically “upregulated” in the brain, which means that these receptors rapidly increase in number and density in response to TBI. According to a 2015 study in Neurotherapeutics, “Upregulation of CB2 with no changes in CB1 have been found in TBI.”

Preclinical research has shown that CB2 receptor signaling mitigates many of the molecular processes that underlie neuronal deterioration and cell death after TBI. In 2012, the Journal of Neuropsychiatric Research reported that CB2 receptor activation attenuates blood-brain barrier damage in a rodent model of TBI. Two years later, the Journal of Neuroinflammation noted that the CB2 receptor is instrumental in regulating inflammation and neurovascular responses in the TBI-compromised brain. Genetic deletion of CB2 worsens the outcome of TBI in animal tests, underscoring CB2’s neuroprotective function.

Other studies have shown that CB2 receptor activation promotes cell repair and survival following an ischemic injury. CB2 receptors are present in progenitor (“stem”) cells and are instrumental in driving neurogenesis (the creation of new brain cells). Neurogenesis enhances motor function and overall recovery after TBI. CB2 knockout mice have impaired neurogenesis.3

Shipwrecked

Research involving animal models has shed light on the pathological processes that ensue after a closed head injury. But promising leads focusing on the CB2 receptor have not translated into successful clinical results. As Italian scientist Giovanni Appendino remarked: “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects.”

But why? For starters, preclinical models only partially reproduce a disease. And synthetic cannabinoids that target a single type of receptor only partially reproduce the multifunctional activities of endogenous cannabinoids and the broad spectrum profile of plant cannabinoids.

Endocannabinoids and phytocannabinoids are “pleiotropic” agents that interact directly and indirectly with several receptors – not just CB1 and CB2 – which also contribute to remediating the neurodegenerative cascade that ensues after a stroke or TBI.4

It appears that an exogenous cannabinoid, either synthetic or plant-derived, may need to engage both CB1 and CB2 (directly or indirectly) and perhaps other pathways, as well, to confer a clinically-relevant neuroprotective effect. A synthetic single bullet aimed at CB2 or another target is simply not as versatile or as effective as a whole plant synergistic shotgun or a multidimensional endogenous entourage.

A promiscuous compound

Cannabidiol is considered to be a promiscuous compound because it produces numerous effects through dozens of molecular pathways. Writing in 2017, Mayo Clinic neurologist Eugene L. Scharf noted that the scientific literature has identified more than 65 molecular targets of CBD. This versatile plant cannabinoid is highly active against brain ischemia, modulating many of the molecular and cellular hallmarks of TBI pathology.

CBD has been shown to reduce brain damage and improve functional recovery in animal models of stroke and TBI. According to a 2010 report in the British Journal of Pharmacology, CBD normalizes post-ischemic heart arrhythmia and limits the size of damaged tissue when administered after a closed head injury.

What’s more, CBD produces no intoxicating side effects, no THC-like high. And CBD use does not lead to tolerance.

A damaged brain can be remarkably plastic, but there is only a circumscribed window of opportunity (the “platinum ten minutes” or “golden hour”) for therapeutic intervention to prevent, attenuate or delay the degenerative domino effect that occurs during a secondary injury cascade. Cannabidiol expands that window of opportunity. Researchers have learned that CBD can convey potent, long-lasting neuroprotection if given shortly before or as much as twelve hours after the onset of ischemia.

Although it has little direct binding affinity for cannabinoid receptors, CBD confers neuroprotective effects and other benefits via several non-cannabinoid receptors. In 2016, scientists at the University of Nottingham (UK) reported that CBD protects the blood-brain barrier from ischemia-induced oxygen and glucose deprivation by activating the 5-HT1A serotonin receptor and the PPAR-gamma nuclear receptor. CBD also acts through numerous receptor-independent channels – for example, by delaying endocannabinoid “reuptake,” which increases the concentration of neuroprotective endocannabinoids in the brain.

Spanish scientists, presenting at the 2016 conference of the International Cannabinoid Research Society, compared the impact of CBD and hypothermia (cooling) on newborn piglets deprived of oxygen because of an ischemic injury. Hypothermia is typically the go-to therapy for treating newborn infants after a stroke. But in this animal model, the administration of CBD was more effective than hypothermia in protecting neonatal brain function. Preliminary data suggests that a synergistic combination of CBD and hypothermia may produce the best results.

CBD for CTE

Chronic traumatic encephalopathy (CTE), a particularly severe form of TBI, is caused by the accumulation of numerous concussions, which increases the risk of neurological problems later in life and hastens the progression of dementia. Football players are particularly vulnerable given the violent nature of the sport.

After years of official National Football League neglect and cover-up, a cascade of suicide and mental health disorders among former star athletes has generated public attention. So has CBD. The anecdotal benefits of CBD-rich cannabis oil for CTE are well known among football players, boxers, and other professional athletes who are prone to head injuries.

CBD, in and of itself, has a unique, broad-spectrum profile that can augment multiple aspects of our innate, endocannabinoid biology. As a single-molecule compound, CBD has delivered impressive neuroprotective results in preclinical experiments. But let’s not forget about THC, given that TBI patients who tested positive for THC did better than TBI patients who abstained from cannabis.

The entourage effect is real. CBD works even better when combined with THC and other constituents of the cannabis plant. Beyond CBD and THC, dozens of cannabis components with specific medical attributes interact synergistically so that the therapeutic impact of the whole plant is greater than the sum if its parts.

For many TBI patients, it’s late in the game and the clock is ticking. A phytocannabinoid remedy that combines CBD and THC and acts at multiple targets simultaneously would seem to be an ideal therapeutic candidate to treat TBI. Thus far, however, there have been no FDA-sanctioned clinical trials to ascertain the efficacy of whole plant, CBD-rich cannabis oil for traumatic brain injury. And in many places, cannabis is still not available as a legal therapeutic option.

Complementary Therapies for TBI

A pathology as complex as a stroke or a traumatic brain injury can benefit from a multifaceted treatment regimen that encompasses a combination of healing modalities, including:
Whole plant cannabis oil. CBD-rich extracts with as much THC as a person is comfortable with.
Terpenes. Cannabis products and strains with beta-caryophyllene and terpinolene.
Diet. A high fat/low carbohydrate/low sugar diet with plenty of leafy greens, omega 3 oils (DHA, EPA), and fermented foods (probiotics).
Nutritional supplements and antioxidants. Magnesium, vitamin D, curcumin, glutathione – and melatonin to restore circadian rhythms and sleep.
Ancient therapies. Acupuncture, exercise, and caloric restriction (fasting), which increase endocannabinoid levels.
Modern therapies. Neurofeedback, low-level laser therapy (photobiomodulation), hyperbaric oxygen, traßnscranial direct current stimulation, flotation tank therapy, and hypothermia (cooling).

Read from source

Societal understanding and conceptualization of what cancer is and what cancer does within the human body has largely been biased by the connotation of the name cancer itself. Many individuals hear the word cancer and immediately think of the horrible consequences of the affliction, but rarely does the question; “What is cancer?”, get raised or answered. According to the National Cancer Institute, at the National Institutes of Health, cancer is a collection of related diseases whose emergence is initiated by the proliferation (or uncontrolled division) of cells without the capacity to stop (Cancer 2015).

Cancer cells originate from mutations in regular cells and these mutations are occurring all the time during our regular lives. The issue of cancer arises when the cells lose the capacity to recognize inhibitory signals from surrounding cells and the resulting cancer cell begins to divide and grow uncontrollably (Cancer 2015). Cancer is a failure of cells to undergo controlled cell division (a natural process involved with wound healing and the replacement of cells on a daily basis).

Research and investigation into novel treatments for cancer have evolved significantly in recent years to consider many different chemicals that originate from plant derived toxins. An example of this is the drug Taxol (the registered trademark named for the drug) or Paclitaxel which, during its original pre-clinical trials, “showed effectiveness against mammary tumours and ovarian cancer” (National Cancer Institute n.d.). Taxol is one of the most recognizable and well-known naturally-sourced plant molecules used in the formulation of a cancer treatment. The origins of paclitaxel begin in the bark of the Pacific yew tree which Agriculture and Agri-Food Canada refer to as a a substance that “can be quite poisonous to humans and livestock” and they even recommend that “no one should attempt self-medication” (Agriculture and Agri-Food Canada, 2013).

Present costs for Taxol are not inexpensive either. The cost of treatment for one patient is $10,000.00 per patient per cycle and costs can increase to $100,000.00 following a ten-cycle treatment period. The costs of treating cancer with this treatment in mind is very expensive.

These enormous associated costs, such as mentioned above, raise viable questions about whether alternative medicines should be sought for the treatment of cancer and it’s symptoms. One of these questions is whether natural plant-derived chemical treatments should be investigated further, and to what extent? This pursuit raises question about an option that has metaphorically been kept behind bars for decades. The United States of America presently classifies marijuana as a Schedule I drug which asserts that it has no present medical benefits and even aggregates the plant with compounds such as heroin, ecstasy and LSD. Schedule I describes the drugs within its classification as containing the “most dangerous of all the drug schedules with potentially severe psychological or physical dependence” (DEA n.d., A).

The investigation of natural plant products capable of treating symptoms of cancer and treating the cancer cells themselves are restricted by the assertion that, as a schedule I drug, marijuana is somehow more dangerous than Taxol – a product capable of killing an individual due to the mitotic spindle poison compounds (capable of disrupting cell division) (Agriculture and Agri-Food Canada, 2013).

Marijuana is described by many American laws, and according to the DEA as possessing no “accepted medical use in treatment,” and for possessing a “lack of accepted safety for use of the drug or other substance under medical supervision” (DEA n.d., B). This assertion is claimed by the DEA, but it should be noted that the the United States of America, as represented by the Department of Health and Human Services presently holds the Patent – “US 6630507 B1 – Cannabinoids as antioxidants and neuroprotectants” which is suggestive that there is some implication of a medical benefit despite the DEA’s claims of no accepted medical use in treatment (DEA n.d.; B Hampson et al., 2003). The allowance of such a patent questions whether other possible treatments for various disease states may exist – considering that present cancer treatments use many other naturally-derived plant models for the derivation of treatments. There seems to be a bias on who is allowed to make such investigations, but the existence of clinical trials involving marijuana are not completely absent from records in the United States and this piece of evidence encourages all of our readers to draw their attention to some of the preliminary evidence derived at this link (a summary of some findings will follow): http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page5 (Cancer 2014).

Thorough investigation of the evidence on this website will require a multi-staged approach, and because of this I plan to begin an episodic investigation into each of the various clinical investigations mentioned, in order to provide an overview for both our readers, and for the scientific community who may not have otherwise been made aware that such trials have even been conducted (or may not have heard of the results and early findings). The next paragraphs will serve to emphasize some of the integral pieces of evidence raised by clinical trials. In future articles, more emphasis will be placed on the trials that investigated specific treatment protocols and related findings.

First, lets take a look at the investigated areas (areas we will focus upon in future articles). As mentioned on the National Cancer Institute Website; antiemetic (anti-nausea), appetite stimulation, analgesia (pain-relief), and lastly, anxiety and sleep. These are some of the permitted studies that examine the effectiveness of cannabis and cannabinoids, but it should be recognized that the capacity to engage in clinical trials for investigation of the viability for cannabis and cannabinoids is extremely limiting and restricted due to DEA enforcement.

For the focus of this article we will raise a few of the observations of the clinical trial with respect to antiemetic properties of strictly cannabis (omitting results from cannabinoids) (Cancer 2014). According the the National Cancer Institute’s investigation, the efficacy of  inhaled marijuana was investigated during three separate trials, in patients who experienced chemotherapy-induced nausea and vomiting (Cancer 2014). In two of the three trials, the use of inhaled cannabis was made available to the patient after the synthetic compound dronabinol (a synthetically derived THC compound recognizable by the brand name Marinol) failed to relieve the symptoms (nausea and vomiting) (Cancer 2014).

In the first trial, patients receiving the treatments cyclophosphamide or doxorubicin were not shown to exhibit statistically significant relief of symptoms (Cancer 2014). In the second trial, a positive result was shown and a statistically superior result was observed in the reduction of these negative chemotherapeutic effects. (Cancer 2014). These results were recorded for patients receiving high-dose methotrexate (Cancer 2014). These results are suggestive that further investigation should be strongly encouraged, since a statistically significant result was observed. Lastly, in the third trial a more complex trial was initiated that involved a “randomized, double-blind, placebo-controlled, cross-over trial involving 20 adults in which both inhaled marijuana while oral THC levels were evaluated.” Although one quarter of the patients reported a favorable reduction of symptoms, there was no report compiled, and the findings were never published (Cancer 2014). Among these three trials (each of which involved patients receiving differing chemotherapy treatments), there was statistical significance observed in 33% of trials. Unfinished, unpublished results in 33%. And lastly, no antiemetic effect in 33%.

The results of these compiled investigations are not enough to determine whether any true antiemetic properties exist for cannabis, but the prospect does exist considering that one of these two studies have conclusive results which suggest statistically significant relief of nausea and vomiting symptoms (Cancer 2014). Based upon these findings, the evidence from these two completed trials should serve as a template for future investigation as far as relief of symptoms in patients who experienced chemotherapy-induced nausea and vomiting. We at MMJ.Today encourage all our readers to keep an eye out for our next investigative focus on the human clinical trials conducted using cannabis and cannabinoids in relation to cancer treatments and relief of symptoms. It is our goal to investigate the scientific prospects in a budding industry, with the aspiration that we may excite the investigation of prospective and novel techniques in treating symptoms of both cancer, as well as many other disease states.

References:

  • Agriculture and Agri-Food Canada. (2013). Taxus brevifolia Nutt. (Pacific Yew). Accessed on April 2nd, 2015. Retrieved from http://www.agr.gc.ca/eng/science-and-innovation/science-publications-and-resources/resources/canadian-medicinal-crops/medicinal-crops/taxus-brevifolia-nutt-pacific-yew/?id=1301435640373
  • Cancer. (2015). What is cancer?National Cancer Institute and the National Institutes of Health. Accessed on April 2nd, 2015. Retrieved from http://www.cancer.gov/cancertopics/what-is-cancer
  • Cancer. (2014). Cannabis and cannabinoids: human clinical studies. National Cancer Institute and the National Institutes of Health. Accessed on April 2nd, 2015. Retrieved from http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page5
  • DEA. (n.d.). A. Drug schedules. U.S. Drug Enforcement Adminitration and United States Department of Justice. Accessed on April 2nd, 2015. Retrieved from http://www.dea.gov/druginfo/ds.shtml
  • DEA. (n.d.). B. Drug fact sheet: marijuana. Drug Enforcement Administration. Accessed on April 2nd, 2015. Retrieved from http://www.dea.gov/druginfo/drug_data_sheets/Marijuana.pdf
  • Hampson AJ, Axelrod J, Grimaldi M. (2003). Cannabinoids as Antioxidants and Neuroprotectants. Patent No. US 6,630,507 B1. Date: 10/7/2003. U.S. Patent and Trademark Office.
  • National Cancer Institute. (n.d.). Success story: taxol (NSC 125973). National Cancer Institute. Developmental Therapeutics Program. Accessed on April 2nd, 2015. Retrieved from http://dtp.nci.nih.gov/timeline/flash/success_stories/S2_taxol.htm