Cancer research and cannabinoids

Cannabinoids: its role in the control of inflammation, emesis and dysmotility in the gastrointestinal tract

Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD

August 15, 2018

Introduction

Using medical cannabis in medical practice, one stumbles on incidental anecdotal symptoms that are relieved including effects on the gastrointestinal tract.

With the advent of cannabinoids, more and more conditions are determined to be helped with its use. This includes the conditions affecting the digestive tract. This explores the role the endocannabinoid system has in the homeostatic activities of the gut and the use of cannabinoids in maintaining this. The endocannabinoid system appears to participate in a regulatory role including maintaining motor and sensory function, maintenance of the epithelial layer and regulate the microenvironment.


Endocannabinoid system and GI motility

It appears that CB1 activation ameliorates gastrointestinal motility under normal physiologic conditions whereas the CB2 receptor seems to modulate it under abnormal conditions such as autoimmune or anti-inflammatory conditions (1).

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Endocannabinoid system and pain in the GI tract

Studies have found that there is an interconnection of the TPRV and cannabinoid receptors in affecting visceral pain from stress-related causes and from underlying pathophysiologic conditions. CB1 likely modulates the TPRV receptors causing a reduction of these receptors, whereas the CB2 receptors counteracts the pain effects of mediators of inflammation on the afferent nerves of the visceral organs (2).

Endocannabinoid system and irritable bowel syndrome

Because irritable bowel syndrome has a certain extent of inflammation, this may be a mechanism by which cannabinoids help with the process (2).

Endocannabinoid system and inflammatory conditions of the GI tract

In one study in the animal model, it was found that the endocannabinoid system has an impact the permeability of the GI tract in either a positive or negative fashion. Cannabidiol (CBD) and Tetrahydrocannabinol (THC), 2 of the most well-studied phytocannabinoids, have the capacity to reverse this permeability of the GI tract that is associated with inflammation (3).


Cannabinoids and nausea

Nausea is one of the most well-known and earliest established symptom treated with cannabinoids. Nabilone which has cannabinoids has been used in treating oncologic patients undergoing chemotherapy to ameliorate the nausea that often accompanies this treatment.

In one study of 110 pediatric patients were studied between December 2010 and August 2015 using nabilone. 20% of the patients developed somnolence, euphoria was seen in 3.6% and dizziness was seen in 10%. In 83 patients with chemotherapy causing high rates of emesis, 50% had complete resolution of chemotherapy-induced vomiting. In 23 patients with chemotherapy with moderate rates of emesis, vomiting control was achieved in 53.8% (4).

Role of cannabinoids in the liver

The endicannabinoid system comprises of the CB1 and CB2 receptors, enzymes and endocannabinoids. The CB1 receptor is found to be pro-fibrinogenic in liver cirrhosis and CB2 receptor is found to be anti-fibrinogenic (5).

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This is info only not medical advice.

Reference

1.Duncan, M., Mouihate, A., Mackie, K., Keenan, C.M., Buckley, N.E., Davison, J.S., Patel, K.D., Pittman, Q.J., Sharkey, K.A. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointesintal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol. 2008, July, 295 (1):G78-G87

2. Pesce, M., D’Alessandro, A., Borelli, O., Gigli, S., Seguella, L., Cuomo, R., Esposito, G., Sarnelli, G. Endocannabinoid-related compounds in gastrointestinal diseases. J. Cell. Mol. Med 2018, Feb., 22(2):706-715

3. Alhamorumi, A., Wright, K.L., Larvin, M., O’Sullivan, S.E. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. Br. J. Pharmacology. 2012, Apr. 165(8):2598-2610

4. Polito, S., MacDonald, T., Romanick, M., Jupp, J., Wiernikpwski, J., Vennetilli, A., Khanna, M., Patel, P., Nin, L., Dupuis, L.L. Safety and efficacy of nabilone for acute chemotherapy-induced vomit in pediatric patients: a multicenter, retrospective review. Pedr. Blood cancer. 2018, Jul. 26:e27374

5. Dibba, P., Li, A.A., Cholankeril, G., Iqbal, U., Gadiparthi, C., Khan, M.A., Kim, D., Ahmed, A. The role of cannabinoids in the setting of cirrhosis. Medicines (Basel). 2018, Jun 9:5(2). pii E52

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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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Introduction/Disclaimer

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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