Tag Archives: medical marijuana

Tumor

The state of medical marijuana in urologic tumor burden control through inflammation reduction and reduction of tumor cell proliferation in cell cultures

IMG_0923_previewVirginia Thornley, M.D., Neurologist, Epileptologist

March 10, 2018

Introduction

Cannabinoids, which are cannabis plant-based non-synthetic medications including cannabidiol (CBD) and tetrahydrocannabinol (THC), are being used more frequently in palliative care to reduce the pain associated with end-stage cancer. In addition, it is well-established that it helps with lack of appetite found in cancer patients and reduces nausea and vomiting associated with many of the chemotherapeutic drug regimens (2), although current studies are needed given the newer chemotherapeutic agents available. Although there were more reported side effects using cannabinoids including euphoria, dizziness, dysphoria, and somnolence it is not clear if low dosages were used or what the ratio of cannabidiol to THC was used. It is well known that using higher doses of THC products will control the pain more adequately but at high doses may cause the side effect. Cannabidiol alone has no intoxication or euphoria and a low dose of cannabidiol combined with THC will ameliorate some of the side effects of THC.   Questions regarding its anti-tumor properties often arise which physicians managing patients with cancer are not prepared to answer. Since most of the studies are done in animal models and are often difficult to translate into the human model, research is needed with randomized clinical trials in the patient population. Currently, most anti-tumor literature is found in cell culture lines and extrapolated. The future is promising but large human studies are needed.

In renal cancer

Cannabinoids work through 2 receptors CB1 found in highest numbers in the brain and CB2 which is predominant in the immune system. In renal cancer, the CB1 receptor is found to be lower in number which may suggest that a reduced number of cannabinoid receptors leads to less control over the proliferation of tumor cells. There is a high concentration in the proximal convoluted tubule which suggests that a down-regulation may be associated with less inhibition of tumor cell proliferation (1). In another study, CB1 receptors were similar in chromophobe tissue lines were similar to renal cells with no tumor. This may serve as a diagnostic tool for differentiating it from clear cell tumors. It is often difficult to differentiate between the two. Chromophobe tumors have the same number of CB1 receptors while clear cell carcinomas have less CB1 receptors. This is important from the histological and diagnostic standpoint (1).

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In prostatic cancer

In prostate cancer, some mechanisms suggested through studies include working through phosphatase induction. It was found that CB1 and CB2 are expressed during later stages of prostatic cancer. Treatment of prostate cancer culture cells with cannabinoids was found to reduce the multiplication of tumor cells, suggesting a role through apoptotic mechanisms. The effect was dependent on dosage. In another study, cannabinoids were found to increase cytokine IL-6 in prostate cancer that is androgen resistant. This suggests that CB2 agonists may play an important role in reducing epithelial cell proliferation and may lead to a means to treat prostatic cancer (1). More studies are needed to elucidate mechanisms leading to treatment of prostatic cancer.

In bladder cancer

There is much evidence that inflammation found in cancer may lead to the metastatic stage. Cancer can lead to a pro-inflammatory state inducing cytokine and growth factor release leading to the environment conducive to metastasis and invasion of cancer cells into other tissues. In one study of the CB1 and CB2 receptors, it was found that activation of CB1 receptors played an important role in regulating tumor cell proliferation while CB2 was important in influencing an inflammatory state (1). Further studies are needed to further elucidate the mechanisms of cannabinoids on bladder cancer.

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Reference

  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. Smith, et al, “Cannabinoids for nausea and vomiting in adults receiving chemotherapy,” Cochrane Database Syst. Rev., Nov., 12(11):CD009464. doi: 10.1002/1465
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Epilepsy

Cannabidiol: mechanisms and efficacy in medically refractory epilepsy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 9, 2018

Introduction

One of the most challenging therapeutic goals are to keep patients with epilepsy seizure free. Once a patient is found to be medically refractory, it is not unusual to find patients on 3-4 medications for seizure control. However, oftentimes, the means to the end is often wrought with its own challenges with patients suffering side effects placing their quality of life secondary to the medical control of their condition. More and more patients and their families are turning towards a more naturalistic approach including diet and cannabidiol use which has fewer side effects as a means to control seizures. The literature is fraught with a paucity of scientific data with small clinical trials, animal models, and anecdotal data. Larger clinical randomized control trials are pursued.

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Mechanisms of Cannabidiol and THC

In the brain, there is the natural endocannabinoid system. Endocannabinoids are released after exercise referred to as the runner’s high which contributes towards our sense of well-being. In the endocannabinoid pathway, cannabidiol has a low affinity to the CB1 receptor and modulates THC tetrahydrocannabinol by blocking CB1 receptor. It is thought to modulate THC by blocking the CB1 receptor acting as an inverse CB1 agonist (2). This may be the mechanism behind combining CBD with THC, CBD modulates the side effects of THC making it less available to exert its effects. Delta9THC is found to work at the level of the CB1 receptors which are rich in the brain and CB2 receptor which is more predominant in the immune system. THC can bind to other targets exerting inflammatory properties. CBD has less binding capabilities to CB1 receptors and is thought to exert its effect by working through other mechanisms such as voltage-gated potassium and sodium channels and the GRP55 in controlling seizures. Cannabinoids are lipid binding or lipophilic making it less available within the system making it challenging to deliver (3).

Cannabidiol clinical trials

In one study, 216 patients were enrolled and followed 3 months after administration of the first dose cannabidiol. Initially, the dose was 2mg/kg which was titrated up to 50mg/kg. 76% were enrolled in the safety profile study and 64% were enrolled in the efficacy profile study. In the first group for safety, 20% had Dravet syndrome and 19% had Lennox-Gastaut syndrome. Side effects were noted in 79% of the patients in the safety group. These include somnolence, diarrhea, seizures (11%), fatigue and reduced appetite. Five disenrolled due to adverse effects, 30% had serious side effects including 1 death of consisting sudden death syndrome. 12% had serious side effects including status epilepticus which may have been related to cannabidiol use. The median reduction of seizures was 36.5%. The study concluded that cannabidiol may be an effective strategy for reducing seizures in medically refractory seizures. The flaw with the study is that the doses at the higher end may have been too high for the patients to tolerate, a lower titrated dose may have been equally effective in controlling seizures and minimizing side effects. Nevertheless, the results were promising as it proves to be beneficial in controlling some of the seizures.

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References

  1. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
  2. McPartland, et al, “Are cannabidiol and 9 delta tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review,” British Journal of Pharmacology, 2015, Feb., 172(3):737-53.
  3. Gaston, et al, “Pharmacology of cannabinoids in the treatment of epilepsy,” Epilepsy Behavior, 2017, May, 70(Pt B):313-318.

 

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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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