Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D. Neurologist, Epileptologist

Introduction

The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010.  Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.

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How it works–the nitty gritty

Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly.  Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated.  CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.

Current legal state of affairs

Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law.  In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store.  Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.

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In conclusion

In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.

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Epilepsy, Glaucoma, pain, Peripheral neuropathy, Tumor

Medical Marijuana: why the huge disconnect between physicians, laws, policies, and patients?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 11, 2018

Introduction

A patient comes to you asking “Doc, my seizures are getting worse, I really hate the side effects of my medications, I really want to go a different route. Have you heard about medical marijuana?” You start sweating profusely, fidgeting in your seat, thinking of every single reason why not to recommend it and come up with  the standard response, “uh, well, I’m not qualified to recommend it and it’s not FDA approved, plus we don’t really know much about it there could be so many side effects.” And then we have the oldie but goodie response, “there’s not enough large randomized control trials to recommend it.” This scene plays 100,000 times over if not a million times over in physician offices across the country. Patients who are disillusioned with adverse effects of medications are looking towards alternative therapy. As surprising as it sounds, patients with chronic pain do not want to get intoxicated by opioids. In fact, some want to be tapered off of them or refuse them all together. Patients with end-stage cancer at the terminal stage of their lives wish to live a comfortable and humane existence without the need for more chemotherapeutic medications or pain medications that consistently make them feel like a zombie. While other patients with epilepsy may be on 4 different anti-epileptic agents and can no longer function or have a good quality of life because of side effects. There are two sides to every coin.

Why you should be educated on cannabidiol and THC use in medical conditions

If patients do not get their answers from their trusted physicians who they trust with their well-being, their health, the temples of their souls, they will go to great lengths in procuring this knowledge. This is via various sites on the internet some of the dubious nature others are from high quality companies that have been in business even before this seeming treatment fad started. Or, the information may be obtained from their brother-in-law’s friend’s hair stylist who is now pain-free after going through a long course of pain medications including ablative treatments, physical therapy, and acupuncture and has a physician who does recommend it. Like it or not, cannabidiol and tetrahydrocannabinol are alternative treatment options and are gaining more and more traction. To ignore it is to be complacent with the changing direction and landscape of medicine. As patients become more and more disillusioned by the limitation of conventional treatments, attention is directed towards alternative regimens. It is not just for the yoga-practicing patient looking for more natural methods, one sees the sweet 83-year-old gentleman who must be someone’s grandfather with the chronic hip pain of 50 years who have failed opioids and is simply looking for pain relief.

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Is there any evidence that it works?

The endocannabinoid pathway is found naturally in the system. It is responsible for the runner’s sense of wellbeing one gets after a 5-mile run and the pleasant mood you get after a 1-hour work-out with Zumba. There are 2 receptors in the system CB1 receptor which has the highest number of brain cells and the CB2 receptor which is found predominantly in the immune system. There are 2 common cannabinoids cannabidiol and tetrahydrocannabinol which exert various medical effects. Cannabidiol (CBD) has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria that one gets from tetrahydrocannabinol, the bane of every ER physician. Unfortunately, the side effects of euphoria of THC have preceded its popularity as a medical product. Little do we know it was once used for hundreds of years as a medication before the psychoactive properties were exploited for recreational purposes. In urologic culture cell lines, it is found that cannabinoids may reduce proliferation of cancer cells and reduce the pro-inflammatory microenvironment that is necessary for metastatic conditions (1). Human studies are still needed to determine a reduction in tumor loads. THC receptors are found in retinal cells and may be found to reduce intraocular pressure in glaucoma (5, 6). Cannabidiol is found to bind to the 5HT1 receptor which reduces anxiety. THC has been well-established in the mouse model to promote the inhibitory control of excitatory pathways in the hippocampus, where seizures commonly arise (8). There is an increase in CB1 receptors after prolonged seizures suggesting a compensatory response.  It has been used in combination and found in several randomized control trials to reduce the frequency of seizures by as much as 36% in medically refractory patients (2). It is well-established that cannabinoids reduce pain refractory to conventional medications (3). It has been found in bench research to be an antioxidant and have anti-inflammatory properties (4, 7). Some studies cite side effects of somnolence, nausea, dysphoria, however, it is not clear what was the quality of cannabinoids or dosages were used. At high doses, while THC can reduce pain it may also result in side effects, which is why it is usually used in combination with CBD which ameliorates the side effects of THC.  In addition, cannabidiol by itself has no euphoria and it takes 100 times the amount to achieve intoxication seen with THC use. Synthetic products will have more side effects than products that are organic meaning only of natural materials.

Given the huge amount of evidence in several different medical conditions (3), the results should overwhelmingly be towards a push in using cannabinoids more frequently. However, because of the cynicism of the public, physicians even of patients, who have been exposed more frequently to the harmful psychoactive side effects, the benefits are far overshadowed. More clinical randomized controlled trials are needed. Most literature cites small numbers of patients enrolled in studies or review multiple medical centers where the conditions are not uniform. In addition, some of the patients that would benefit the most are the least in numbers such as those with rare neurological conditions such as Dravet syndrome or Lennox-Gastuat syndrome.

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In conclusion

As it still stands, many states still do not recognize the medicinal value of cannabidiol or tetrahydrocannabinol. In some states, medical physicians are not allowed to recommend it and put themselves at risk for FBI questioning in even suggesting its use. It is not uncommon for patients to move states or order from other states or countries to procure this liquid gold that is supposed to work wonders. Only time will tell if this is a passing fad and if there are long-standing side effects, however, as of current standing, medical marijuana is here to stay. As far as the literature goes, there are beneficial results but it is a cautionary tale as more studies in large human trials are still needed. As with any new preclinical data, the preclinical status may get ahead of itself and human trials do not replicate the desired results. But from the small clinical trials in seizures, pain, nausea, anxiety, and loss of appetite, the results are promising while more research is needed for anti-tumor effects in humans.

As with any medication, there will be clear-cut side effects just as with any other medication which is why more studies are needed to determine the least amount with the least amount of side effects. In some studies,  amounts upwards of 50mg/kg (2) is used the high amounts likely responsible for causing side effects, which is far higher than that cautioned by medical marijuana dispensaries. It will take patients time to wrap their heads around taking guidance from a fresh-faced 20-year-old millennial at the spa-like dispensary which is currently the norm at most dispensaries, who likely knows much more than even most medical professionals. It seems it will take even longer in Congress to understand the potential benefit of cannabinoids from a medical standpoint especially with the present opioid epidemic. Countries in Europe have far surpassed the United States when it comes to cutting-edge treatments. Perhaps, it will take even longer for the medical community to see the medical potential with their exposure to the sinister side of tetrahydrocannabinol seen in patients in the ER for non-medical reasons, which may be one of the most challenging stumbling blocks.

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Introduction/Disclaimer

References:

  1. Ghandhi, et al, “Systemic review of the potential role of cannabinoids as anti-proliferative agents for urological cancer,” Can. Urol. Assoc. J., 2017, May,-April., 11(3-4):E138-E142.
  2. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
  3. Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88.
  4. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
  5. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  6. Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
  7. Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
  8. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.
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Peripheral neuropathy

Peripheral neuropathy: chronic pain amelioration with cannabidiol and tetrahydrocannabidiol

Virginia Thornley, Neurologist, Epileptologist

March 8, 2018

Introduction

Chronic pain from neurological conditions such as neuropathic pain can become refractory to conventional medications. Interest is directed towards novel ways of treatment such as cannabidiol and THC which are known in animal models to be anti-inflammatory, analgesic and neuroprotective. Cannabinoids are being used more commonly in patients who have failed medical treatments and remain a viable option in the treatment of pain. Many animal models point towards mechanistic evidence that cannabidiol and THC reduce severity and frequency of pain syndromes. Cannabidiol is non-intoxicating and is an alternative form of management. With THC, the level of pain relief is higher but with that comes a higher risk of side effects at greater doses.

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Cannabidiol and neuropathic pain in joints

Osteoarthritis involves inflammation, pain, and neuropathic pain. Cannabidiol was studied in rat models and its effect on pain from the joints and nerves. In end-stage osteoarthritis, cannabidiol reduced joint afferent pain. Transient joint inflammation was reduced using cannabidiol. CBD application used prophylactically demonstrated lack of development of pain and inflammation during later stages.

One study suggests that chronic neuropathic pain might be suppressed by cannabidiol through alpha 3 glycine receptors. In mice lacking these receptors, there is no cannabidiol analgesic effect. Cannabinoids are found to support glycine activity in the dorsal cell neurons in rats. This suggests that glycinergic cannabinoids may provide a potential therapeutic option in treating neuropathic pain. There is lack of psychoactive side effects or development of tolerance (1).

Cannabidiol and neuropathic pain studies

In one review of 15 randomized controlled trials against placebo with a total of 1619 patients, 13 studies consisting of 1565 patients reported a reduction of pain compared to placebo which was statistically significant. There was a frequency reduction in pain of 30%. 10 studies used nasal tetrahydrocannabinol /cannabidiol and 3 used synthetic cannabidiol while 2 used medical cannabis. They concluded that cannabidiols were marginally superior and had greater side effects than placebo. It is a treatment option for patients who have failed several lines of treatment. Some flaws that can be seen in this study is that with this study, some centers used synthetic forms of cannabinoids and others used a combination of THC and cannabidiol. Synthetic medical marijuana has a different quality compared to a product that is purely organic and made from natural materials. High doses of THC is known to cause side effects while with lower doses of THC pain relief may be obtained with fewer side effects. It is not clear how pure the products are which were being administered.

In one large study of 303 patients with peripheral neuropathy, 128 used CBD/THC spray and 118 randomized to placebo. End-point was a 30% responder rate using the PNP numerical scale 0-10. There was a substantially higher number of responders for CBD:THC but not statistically significant. Quality of life and sleep improved in those with CBD/THC nasal spray. They concluded that use of CBD/THC helped improve pain from peripheral neuropathy and there were no substantial adverse effects from the patients studied (3).

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References
  1. Xiong, et al, “Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha 3 glycine receptors,” Journal of Experimental Medicine, 2012, Jun., 209(6):1121-1134.
  2. Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88
  3. Serpell, et al, “A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment,” European Journal of Pain, 2014, Aug., 18(7):999-1012.

 

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Peripheral neuropathy

On pluripotent stem cell research chemotherapy-induced peripheral neuropathy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2018

Introduction

As more and more survivors of cancer grow in number, there is increasing interest in treatments for chemotherapy-induced toxicity. Chemotherapy-induced peripheral neuropathies are one of the most common neurotoxic side effects prevalent in cancer survivors. Attention is drawn to alternative treatments such as stem cell research as at times, this condition may be resistant to treatment with conventional agents.

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Common chemotherapeutic agents that cause neuropathy

Some of the most common chemotherapeutic agents that cause peripheral neuropathy include vincristine, oxaliplatin, cisplatin, paclitaxel. The sites most prevalent with neurotoxic effects include the dorsal root ganglion, peripheral nerves, satellite cells and Schwann cells as well as glial cells in the spinal cord.

Some mechanisms that are proposed that cause neural damage include glutamate activation, increased intracellular oxygen changes, DNA damage, altered cell repair, alteration in ion channels, change in mitochondrial metabolism and MAP kinase activation.

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Role of stem cell in chemotherapy-induced peripheral neuropathy and other novel treatment approaches

In chemotherapy for colon cancer, oxaliplatin can cause chemo-induced peripheral neuropathy in 50% of patients. In one study, pain relieving qualities of mesenchymal stem cells were studied. Rat adipose stem cells were applied to rats with chemotherapy-induced peripheral neuropathy in one animal model. An IV injection of rat adipose stem cell injected into the rate of neuropathy revealed a reduced hypersensitivity to the noxious effects. Repeated injections every 5 days produced the same results. VEGF was noted to be upregulated or vascular endothelial growth factor. When a monoclonal antibody used against this VEGF was applied there was reduced pain, suggesting a role of VEGF in pain. Adult adipose mesenchymal stem cell may represent a novel approach to alleviating pain from chemotherapy-induced peripheral neuropathy. This rat model also elucidated the role an antibody against VEGF can play in the treatment of peripheral neuropathy caused by chemotherapy.

Pain might also be influenced by increased gap junction coupling during chemotherapy. In one study, using a gap coupling blocker, the pain was alleviated in chemotherapy-induced peripheral neuropathy in mice producing an analgesic effect(3).

 

Reference:

  1. Di Cesare, et al, “Adipose-derived stem cells decrease pain in a  rat model of oxaliplatin-induced neuropathy: role of VEGF-A modulation,” Neuropharmacology, 2018, Mar., 15; 131:166-175.
  2. Carozzi, et al, “Chemotherapy-induced neuropathy: what do we know now?” Neuroscience Letter, 2015, Jun., 2(596):90-107.
  3. Warwick, et al, “The contribution of satellite glial cells to chemotherapy-induced neuropathic pain,” European Journal of Pain, 2013, Apr., 17(4):571-80.
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