fibromyalgia

Review of scientific literature: can diet alleviate symptoms from fibromyalgia

Virginia Thornley, M.D., Neurologist, Epileptologist
October 15, 2018
Introduction
There is growing interest in lifestyle changes in controlling certain diseases especially those that are related to inflammation. This seeks to review the scientific literature and determine if there is any science supporting any evidence for recommend dietary changes to alleviate symptoms from fibromyalgia.
Possible mechanisms underlying fibromyalgia
Fructose is a molecule that is not absorbed well in the gut and is related to low levels of tryptophan causing tryptophan to be absorbed less in the gut. Tryptophan is the precursor of serotonin or 5-HT which is found to be low in patients with fibromyalgia (1). Fructose is widely seen in the western diet present in honey and sweeteners known as high fructose corn syrup.
Fructose malabsorption in the gut may contribute towards increased fructose and interefere with tryptophan absorption (1).
Low fructose diet
In one case report a diet was devised where fructose was excluded so as to allow increased tryptophan availablility. The diet consisted of eggs, fish, clams, meat, celery, spinach, beets, dark chocolate, walnuts, carrots, potatoes, chard, grape seed oil, thyme, sage, carob powder, millet, green tea, small amount of almonds, coffee and rosemary. Sodas and processed food were deleted from the list. Legumes, cereal, wheat and fructan-containing vegetables and inulin containing vegetables were excluded. The diet is comprised of 25-27% proteins, 9-10% fiber, 31-36% carbohydrates and 30-32% fats. The patient’s previous diet consisted of the Mediterranean diet which has 50% carbohydrates (2). While fructose may be excluded in a diet, this may reduce the caloric intake which would be detrimental. Any diet that is developed should  not neglect the caloric intake.
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After 12 months, the patient was found to have less pain and could do aerobic exercises due to her pain-free state. There were some times she did not strictly adhere to the diet which resulted in a flare-up of the pain. It is also indicative that a modified diet is not curative short-term. This indicates that the results from the diet are not related to a placebo effect. More studies are needed. This study supports the growing interest of low levels of tryptophan, which is a precursor of 5-HT, as contributing towards the mechanisms causing pain in fibromyalgia (2).
 
Other factors that contribute towards fibromyalgia
Women seem to be more prone to symptoms of fibromyalgia. While the level of 5-HT is similar in men and women, women seem to synthesize 5-HT at a reduced rate compared to men (1).
Stress and anxiety leads to increase of glucocorticoids which may also interfere with 5-HT synthesis (1).
 
In summary
There is increasing biochemical information that fructose may contribute towards the pathophysiology involved in fibromyalgia. Growing interest is directed towards the use of certain diets to control the symptoms of fibromyalgia, however, large clinical human trials are needed.
While there is scientific biochemical information, large human trials are needed. There is not enough information to recommend this until large human clinical trials are performed.
References
1. Lattanzio, S.M. Fibromyalgia syndrome: a metabolic approach grounded in the biochemistry for the remission of symptoms Front. Med. 2017, Nov. 4:198
2. Lattanzio, S.M., Imbesi, F. Fibromyalgia syndrome: a case report on controlled remission of symptoms by a dietary strategy. Front med. 2018, 5:94
This is for informational purposes only and does not constitute medical advice, see your physician. Large human randomized controlled clinical trials are needed.
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multiple sclerosis

Review of literature:  stem cell therapy in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist
October 8, 2018
 
Introduction
Stem cell therapy is explored for certain types of cancer such as bone marrow cancer. Its therapeutic options have been experimentally being expanded to other disease such as multiple sclerosis. This seeks to review some of the literature on current research for stem cell therapy in multiple sclerosis. As yet, there are still ongoing research and experiments and is not yet  approved by the FDA as treatment for multiple sclerosis. This seeks to review mechanisms, small studies and experimental studies in multiple sclerosis.
Some mechanisms through which stem cell therapy may help
Natural killer cells are thought to attenuate Th17 cells which are pro-inflammatory after autologous hematopoietic stem cell treatment. It may not have effect on the Th1 cell but it seems to reduce the number of Th17 cells (1).
Comparing Wharton Jelly mesenchymal cell with bone marrow mesenchymal stem cell
One study shows that Wharton Jelly mesenchymal stem cell may be comparable to the gold standard bone marrow stem cell and may be more easily extracted. There is a different gene phenotype and are found to overexpress genes that impact neurotrophic support making it a great candidate for stem cell source in neurodegenerative diseases such as amyotrophic lateral sclerosis or Parkinson’s disease. It was found to cause greater neuronal maturation in neuroblastoma cells compared to bone marrow mesenchymal cells. Genes that influenced adhesion, proliferation and the immune system were found to be greater expressed in Wharton jelly mesenchymal stem cell (2).
 
aHSCT in fatigue
In one small study in 23 patients the use of autologous human stem cell treatment helped with symptoms of fatigue using the FIS or the fatigue impact scale (1). The median score in FIS was reduced by 36% with 4 patients with a complete reduction. Some even had gainful employment and returned to driving, measured with the EDSS or expanded disability status scale(3).
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A pilot study shows mesenchymal stem cell injection slows progression
In a pilot study of 4 patients, 3 had secondary progressive type while 1 was in the relapsing-remitting stage. Autologous bone marrow stem cells were injected and patients were followed for 2 years. Those with secondary progressive type stabilized with no further deterioration while the patient with relapsing remitting type had an attack. None of the MRI tests showed any new plaques or abnormalities(4).
Mesenchymal stem cell treatment is thought to be helpful as a neuroprogenitor and slows the neurodegeneration where standard medications may be ineffective (5).
Hematopoietic cell transplant  for relapsing-remitting multiple sclerosis
In one study of 25 patients looking at high dose immunotherapy and autologous hematopoietic stem cell therapy, peripheral blood stem cell grafts were CD34+ chosen. Immunosuppression was given beforehand. It was found to reduce relapses over a course of 3 years in patients with relapsing-remitting multiple sclerosis without serious adverse effects(6).
In summary
There is growing interest in stem cell therapy as a novel treatment in multiple sclerosis.  Research has shown that Wharton’s jelly from the umbilical cord may have features making it a better therapeutic alternative compared to bone marrow mesenchymal stem cells. So far, small studies have shown promise. Larger human trials are needed.
Reference
    1. Darlington, P.J., Stopnicki, B., Touil, T., Doucet, J.S., Fawaz L.,  Roberts, M.E., Boivin, M.N., Arbour, N., Freedman, M.S., Atkins, H.L., Bar-Or, A., Canadian MS/BST Study Group. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting Multiple Sclerosis. Front Immunol. 2018, 9:834
    2. Donders, R., Bogie, J.F.J., Ravanidis, S., Gervois, P., Vanheusden, M., Maree, R., Schrynemackers, M., Smeets, H.J.M., Pinxteren, J., Gijbels, K., Walbers, S., Mays, R.W., Deans, R., Van Den Bosch, L., Stinnissen, P., Lambrichts, I., Gyselaers, W., Hellings, N. Human Wharton’s jelly-derived stem cells display a distinct immunomodulatory and preregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev. 2018, Jan. 27(2):65-84
    3. Bose G., Atkins, H.L., Bowman, M., Freedman, M.S. Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis. Mult. Scler. 2018, Sep: 1352458518802544 (epub: ahead of print)
    4. Sahraian, M.A., Mohyeddin Bonab, M., Baghbanian, S.M., Naser Moghadasi, A. Therapeutic use of intrathecal mesenchymal stem cells in patients with Multiple Sclerosis: a pilot study with booster injection. Immunol Invest 2018, Aug. 29:1-9
    5. Holloman, J.P., Ho, C.C., Huntley, J.L., Gallicano, G.I. The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am. J. Stem Cells. 2013, Jun. 30, 2(2):95-107
    6. Nash, R.A., Hutton, G.J., Racke, M.K., Popat, U., Devine, S.M., Griffith, L.M., Muraro, P.A., openshaw, H., Savre, P.H., Stuve, O., Arnold, D.L., Spychala, M.E., McConville, K.C., Harris, K.M., Phippard, D., Georges, G.E., Wundes, A., Kraft, G.H., Bowen, J.D., High-dose immunosuppressive therapy and autologous hematopoeitic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3 year interim report. JAMA Neurol 2015, Feb. 72(2):159-69

This is for informational purposes only not medical advice see your physician.

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multiple sclerosis

Ketogenic diet: can it play a role in treating symptoms of Multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist
September 19, 2018
@VThornleyMD
Introduction
Multiple sclerosis has no cure at this current moment. It is unclear what is the exact etiology otherwise there would be a cure. Based on research, genetic and environmental factors play a role. Based on MRI observations, there are inflammatory and degenerative components to the pathogenesis.
 
What is the ketogenic diet and how does it pertain the brain
The ketogenic diet was initially found to be effective in treatment of medically refractory seizures. But the underlying concept might be applied to other diseases as well.
Instead glucose as the energy substrate, ketones are utilized, If the supply of glucose is reduced, the energy source is shifted towards the beta-oxidation of fatty acids into ketone bodies. These ketones become the new source of energy and allows increased ATP formation which is the source of energy in the mitochondria, which is the powerhouse of the cell where energy is formed.
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Different lines of thinking regarding pathogenesis of Multiple Sclerosis
There are lines of thought that Multiple sclerosis can be inflammatory versus neurodegenerative. Because of this many agents are directed towards the autoimmune component of the disease process. It is commonly thought that the autoimmune process results in the neurodegeneration seen on MRI.
As evidenced by the “black holes” seen on MRI after acute attacks, there is evidence there is a neurodegenerative aspect. This other line of thinking suggests that it is a degenerative process that triggers the inflammatory response.
It’s been found  that degenerating axons have abnormal mitochondria.
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Ketogenic diet and inflammation
In one animal study, it was found that the ketogenic diet reduced inflammatory cytokines after 14 days in animals (2).
 
Ketogenic diet and increased ATP
In one animal model with a control group and a group on ketogenic diet, after 3 weeks it was found that those on the ketogenic diet had a higher ATP/ADP ratio which is speculated to contribute towards neuronal stability.

How can the ketogenic diet help with Multiple Sclerosis?
The ketogenic diet reduces the formation of reactive oxygen species. It preserves ATP production when the mitochondria fails. The thought is that the axons start to degenerate once the mitochondria are dysfunctional (1).
In summary
There are no human clinical studies on ketogenic diet and the improvement of multiple sclerosis. Based on pre-clinical studies, there is indication that ketogenic diet may help improve the ATP stores when the mitochondria becomes dysfunctional which may potentially slow neurodegeneration of axons.
The ketogenic diet might reduce inflammation which is thought to be triggered by a neurodegenerative process in Multiple Sclerosis. However, more studies are needed especially human clinical trials. Currently there is not enough evidence to support this based on the available studies as pre-clinical studies do not always correlate in human trials. More studies are needed.

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Reference
  1. Storoni, M., Plant, G. The therapeutic potential of the ketogenic diet in treating progressive multiple sclerosis. Mult. Scler. Int. 2015. doi 10.1155/2015/681289
  2. Dupuis, N., Curatolo, N., Benoist, J.F., Auvin, S., Ketogenic diet exhibits anti-inflammatory properties. Epilepsia, 2015. 56(7):e95-98
  3. DeVivo, D.C., Leckie, M.P., Ferrendell, J.S., McDougal, D.B., Jr. Chronic ketosis and cerebral metabolism. Ann Neurol. 1978, Apr. 394):331-337
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multiple sclerosis

Review of literature: can the Wahls diet (modified Paleolithic diet) and low saturated fat Swank diet have any effect on multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist

September 17, 2018

@VThornleyMD

Introduction

Patients are seeking complementary treatments aside from conventional agents. Agree with it or not, if doctors do not listen to their patients they will seek it elsewhere so it is good to be up to date on the review of literature. While alternative treatments are commonly lacking in evidence based medicine it does not necessarily have to work in opposition with conventional agents. There are studies by Mauskop, (1) a headache specialist who found that 50% of migraineurs are magnesium deficient and magnesium can be a effective preventative agent in selected patients. Instead of being instantly dismissive, review of the literature should be sought to have an evidence-based understanding from a scientific level.

What is the modified Paleolithic diet?

In the modified Paleolithic diet, there is stress on meat, fruit and vegetables, excluding legumes, dairy and grains (2). Night shade vegetables such as tomatoes and eggplants are excluded.

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What is the Swank diet?

Dr. Roy Swank from Norway hypothesized that a diet rich in saturated fat likely caused a faster progression of the disease state in multiple sclerosis relapsing-remitting type. He followed 144 patients for 34 years. The patients consumed less than 20g of saturated fat in their diet and followed. It was observed that the relapses and progression correlated with the amount of saturated fat that was consumed. The greatest benefits were seen in those with mild symptoms at the start of the study. The patients were followed 50 years, however, there were no case controls patients for comparision (3).

Review of literature of the Wahl’s diet on Multiple sclerosis

One study focusing mainly on the dietary component seeks to understand an effect using the randomized controlled clinical trial method. The study is ongoing (2). It seeks to study the anecdotal information that diet low in saturated fat may lessen  the debilitating symptom of fatigue in patients with multiple sclerosis. While there have been anecdotal data, many patients have been found to drop out of the control group because of poor tolerability making results unreliable (2). In addition, the studies available provide a multi-prong approach including factors of stress reduction, exercise and muscle stimulation.

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Multimodal approach: exercise, stress reduction, meditation, massage and diet

One small study of 20 patients demonstrated some benefits of modifying diet, reducing stress and stimulating muscles in relation to multiple sclerosis symptoms.  They found that patients who presented with mild symptoms of progressive multiple sclerosis received some benefit to a multi-prong approach with regard to gait improvement compared to those who were more advanced in their disorder (4).

In summary

To summarize, at present there is insufficient data to support the Wahl’s diet as an effective treatment option based on the available current studies.  However, having said that there has been some anecdotal and very small studies indicating benefits in multiple sclerosis. Randomized controlled clinical trials which are the gold standard in research are ongoing which will be shed more light on its effectiveness.

In the meantime, while there are no completed large randomized controlled clinical trials, these types of diets and modalities are complementary with the current treatment and would do no harm. However, until large randomized controlled clinical trials are completed, it is difficult to ascertain if they are indeed effective and recommend it advocating it as effective.

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Reference

  1. Mauskop, et al, All migraine patients should be treated with magnesium. Journ. Neural Trans. 2012, May, 119(5):575-579
  2. Wahls, T., Scott, M.O., Alshare, Z., Rubenstein, L. Darling, W., Carr, L., Smith, Chenard, C.A., LaRocca, N., Snetselaar. Dietary appraoches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: a study protocol for randomized controlled trial. Trial. 2018, Jun. 4, 19(1):309
  3. Swank, R.L., Duggan, B.B., Effect of low saturated fat diet in early and late cases of multiple ssclerosis. Lancet, 1990, Jul., 7, 336 (8706)
  4. Bisht, B., Darling, W., White, E.C., White, K.A., Shivapour, E.T., Zimmerman, M.B., Wahls, T. Effects of a multimodal intervention on gait and balance of subjects with multiple sclerosis: a prospective longitudinal pilot study. Degen. Neurol. Neuromuscul Dis. 2017, Jun. 26, 7:79-93

 

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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).

13919976_10154408563813841_8381429212704620563_o (2)

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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Epilepsy

Dravet Syndrome: morphologic abnormalities, role of precision medicine, novel mechanisms for treatment and treatment options

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

August 13, 2018


Introduction

Dravet syndrome is characterized by developmental delay and intractable predominantly myoclonic seizures related to an abnormality in the SCN1A gene. The SCN1A gene encodes for sodium channel Nav1.1 which is voltage gated. It is one of the most pharmacologically resistant types of epilepsy syndromes.

Functional and morphological studies

One animal study using SCN1a(E1099x/HET mouse model for Dravet syndrome demonstrated early seizures which reached its maximum at post-natal week 4. There were less GABAergic neurons that expressed the Nav1.1 subunit in the dentate gyrus in the Het mice. There was a reduced number of inhibitory inputs travelling to the dentate gyrus cells in the Het mice. There was an increase in transmissions of excitatory impulses. The dentate gyral cells were noted to be abnormal morphologically with less arborization and a greater number of spines(1). This correlated with the abnormal excitation and reduced inhibition.

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Fenfluramine

Fenfluramine has been revisited as a treatment option for Dravet syndrome. It is metabolized into norfenfluramine. Fenfluramine and its metabolite norfenfluramine uncouples the association of sigma 1 receptor from the NR1 subunit of NMDA receptors (glutamate N-methyl-D-aspartate). Fenfluramine has serotonergic activity at the 5HT2AR receptor in addition to the activity at the sigma 1 receptor which reduces convulsive activity. Fenfluramine influences the cannabinoid type 1 receptor uncoupling with NMDARs which allowed greater restriction of the NMDAR actions (2).

Ketogenic diet

Ketogenic diet should not be discounted as a therapeutic option (3). In a study of 52 patients with pharmacoresistent epilepsy, spike and sharp wave complexes were reduced on the electroencephalograms of 26 patients which was significant (p<0.5). After a treatment of 12 weeks, there was a noticeable effective rate if seizure reduction of 42%. Motor, language and cognition was found to be improved in 23 patients, although the degree of improvement was not thought to be significant. Some adverse reactions included digestive problems and elevated liver enzymes.

Precision medicine

Because Dravet syndrome is related to a de novo loss of function mutation, great interest has been generated towards precision medicine. This involves targeting the genetic abnormality with treatments tailored towards a patient’s particular genetic make-up.

In one study using precision medicine, the selective activation of the Nav1.1 through the venom Hm1a restored the inhibitory mechanism of the neurons that are responsible for causing seizures in the mice model for Dravet syndrome (4). This may be a novel target for a therapeutic option using precision medicine in the treatment of Dravet syndrome.

Summary

In summary, while Dravet syndrome continues to be a devastating neurological disorder, there is research in precision medicine and other novel therapeutic options that can pave the way for more studies in this area.



https://neurologybuzz.com/
This is info only not medical advice.

Reference

1. Tsai, M.S., Lee, M.L., Chang, C.Y., Fan, H.H., Yu, I.S., You, J.Y., Chen, C.Y., Chang, F.C., Hsiao, J.H., Khorkova, O., Liou, H.H.,Yanagawa, Y., Lee, L.J., Lin, S.W. Functional and structural deficits of the dentate gyrus network coincide with the emerging spontaneous seizures in an Scn1a mutant Dravet syndrome model during development. Neurobiol Dis 2015, May, 77:35-48
2. Rodriguez-Munoz, Maria, Sanchez-Blasquez, Pilar, Garzon, Javier. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018, May, 9(34):23373-23389
3. Qiong, W., Hua, W., Yu, Y., Mei Zhang, J., Yan Liu, X., Ying Fang, X., Hua Yang, F., Jun Cao, Q., Qi, Ying. Ketogenic diet effects on 52 children with pharmacoresistent epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018, May, 8(5):e00973
4. Richards, K.L., Milligan C.J., Richardson, R.J., Jancovski, N., Grunnet, M., Jacobson, L.H., Undheim, EAB, Mobli, M., Chow, C.Y., Herzig, V., Csoti, A., Panvi, G., Reid, C.A., King, G.F., Petrou, S. Selective Nav1.1 activation rescues Dravet syndrome mice from seiuzres and premature death. Proc. Natl. Acad. Sci. U.S.A. 2018, Aug. pii:201804764

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Cancer research and cannabinoids

Cannabinoids: potential role in the detection and reduction of pancreatic tumor load in pre-clinical studies

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

August 1, 2018

Introduction

Cannabinoids are gaining more recognition in treatment not only of pain, seizures and mood disorder but also in a wide variety of conditions. There have been 3 decades of pre-clinical research studying the mechanisms as it relates to the different organ systems. There has been an exponential increase in cannabinoid research especially in light of the demand by grassroot movements for it availability in treating a wide variety of conditions.

As more and more physicians start to recommend it, more symptoms are coming to light which can be ameliorated with medical cannabis. One of the most sought after answer is the deadliest of diseases which is cancer. This seeks to study the mechanisms by which cannabinoids may play a role in reduction of tumor load.

Studies

There are many studies demonstrating the involvement of the endocannabinoid system in modulating the pathogenesis of tumors.

There are no published human clinical trials using cannabinoids in the treatment of the actual underlying pancreatic cancer. Cannabis is labelled under the schedule 1 classification, with that comes the difficulty with procuring the agent because of the bureaucracy and legal red tape that accompanies it. Regardless, there has been an exponential increase in pre-clinical studies in in vitro and in vivo studies.

Detection of pancreatic duct cancer using a CB2 probe

A study showed that the CB2 receptor is highly expressed in pancreatic duct cancer which seems to correlate with  the aggressiveness of the tumor (1). One study reports on using fluorescence imaging on pancreatic duct cancer using an NIR (near infrared) CB2 receptor targeted probe (2). The study found a high level of expression of CB2 receptors in patient samples with pancreatic cancer compared to normal pancreatic tissue. This is significant because it gives information on a specific target for diagnostic and treatment purposes.

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Cannabinoid involvement in autophagy through the AMPK pathway

In one study the cannabinoid receptor ligands were discovered to cause autophagy and activate AMPK in pancreatic cancer.  In previous works by the same authors, cannabinoids were found to increase the radical oxygen species. In another study ROS was found to interact with the mitochondria where ATP is produced. AMP is upregulated instead leading to AMPK production which reduces mTOR1c and leads to an increase in autophagy and reduction of cell growth (3).

Possible therapeutic role of CB1 and CB2 receptor ligands on pancreatic cancer

In another study using pancreatic cancer cell lines Panc1, 2 cannabinoid receptor ligands were applied to study the mechanisms of cannabinoids and its possible anti-tumor effect. Cannabinoid ligands GW405833 and arachidonoyl cyclopropramide. The study showed that the cannabinoid ligands were involved in the down-regulation and up-regulation of proteins associated with regulation of cell growth and their energy metabolism. This could be a potential target for therapeutic approaches in pancreatic cancer (4).

Synergistic responses occur when CBD is combined with radiation

Cannabidiol can augment the tumor killing potential when combined with radiation therapy in pancreatic cancer which was studied under in vitro studies. Synergistic responses were noted when 5 micrograms of CBD was combined with 4Gy of radiation therapy in a clonogenic assay. In the same study using mice, there was increased survival in mice with pancreatic tumor using CBD compared to a  control cohort. When CBD was added with SRB or smart biomaterials (agents which are sensitive to environmental factors that allow delivery of other agents in this case CBD to the tumor cells) the mice survived compared to the control cohort with just CBD application alone. This study demonstrates that CBD in conjunction with radiation therapy enhances the tumor killing properties in the treatment of pancreatic cancer (5).

SRB’s or smart radiotherapy biomaterials allow the insertion of payloads which allow the abscopal effects of radiation therapy thereby boosting its results (6). Abscopal refers to the idea that radiation treatment can affect tumors distant from the area treated.

In summary

While there may be a dearth of human clinical trials using cannabinoids for treatment in pancreatic cancer, the pre-clinical studies demonstrate that the endocannabinoid system may play a potential role in the mechanisms, diagnosis and treatment of pancreatic cancer, one of the deadliest tumors, and should not be discounted. More studies are needed especially human clinical trials.

This is info only not medical advice.

References

1. Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzman, M., Velasco, G., Iovanna, J.L. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006, Jul, 66(13):6748-55
2. Guo, X., Ling, X., Du., F., Wang, Q., Huang, W., Wang, Z., Ding, X., Bai, M., Wu, Z. Molecular imaging of pancreatic duct adenocarcinoma using the type 2 cannabinoid targeted near-infrared fluorescent probe. Transl Oncol. 2018, Jul. 11(5):1065-1073
3. Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D’Alessandro, A., Zolla, L., Palmieri, M. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 2013, Jun 13, 4 e664
4. Brandi, J., Dando, I., Palmieri, M., Donadelli, M., Cecconi, D. Comparative proteomic and phosphosproteomic profiling of pancreatic adenocarcinoma treated with CB1 and CB2 agonists. Electrophoresis. 2013, May, 34(9-10):1359-1368
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