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.

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.

About

Introduction/Disclaimer

http://neurologybuzz.com

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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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
5. Moreau, M., Yasmin-Karim, S., Kunjachan, S., Sinha, N., Gremse, F., Kumar, R., Fan Chow, K., Ngwa, W. Priming the abscopal effect using multifunctional smart radiotherapy biomaterials loaded with immunoadjuvants, Front Oncol 2018, 8:56
6. Yasmin-Karim, S., Moreau, M., Mueller, R., Sinha, N., Dabney, R., Herman, A., Ngwa, W. Enhancing the therapeutic efficacy of cancer treatment with cannabinoids. Front Oncol 2018 Apr 24 (8):114
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Medical Practice

Demise of medicine: neurologist who advocated for patients is silenced

Virginia Thornley, M.D., Neurologist
@VThornleyMD
https://neurologybuzz.com/

July 30, 2018

Introduction

Many physicians are overwhelmed by patient loads, 10 minute visits, the wealth of documentation dictated by health insurance requirements and the overwhelming overtaking of medicine by non-physician personnel. Wellness programs abound but this only addresses the symptoms of the underlying problem. We see articles and articles abounding online: physician fired or coerced into resignation for speaking about the quality of healthcare placing profits over patients or speaking about non-physicians overstepping boundaries putting patients at risk. Physicians are termed “non-team players” and “disruptors.”  We see non-physicians calling themselves doctors when they are not doctors of medicine but something else other than medicine managing the most complex cases in the hospital setting at times performing duties beyond their limits. NP’s and PA’s see patients, order tests and make decisions on treatment. This is most rampantly seen on the primary care horizon under the liability and license of a physician. Some aggressive organizations of NP’s are now very powerful seeking independent practice, meaning practicing without the supervision of a physician.  They have a place in medicine but their positions were never designed to overtake the skill sets of physicians. Patients are referred in-network in order to increase profitability of that company even when a better physician may be outside of the network. Appointments, which used to be at the discretion of the physician, are now reduced to staring at a computer making sure all the boxes are clicked rather than looking at the patient in the eye to construct their stories. The cancer is the business model at the center which must be ripped out. The minute medicine became profit-centered and not patient-centered was the beginning of the end of healthcare as we knew it. This is the healthcare we face today.

The training of a medical physician

Previously, the connection was straightforward-physician and patient. That connection is sacred which nobody on this earth held, it is that sacred.  https://neurologybuzz.com/2018/06/06/returning-to-the-sacred-relationship-between-patient-and-physician/ A physician’s duty is towards the patient, taking care of them using all the knowledge of the sciences with which they trained for so long. There are 4 years of pre-medical school, 4 years of medical school, 1 year of internship, 3-5 years of residency training and 2-3 years of fellowship. That is 11-17 years of medical training. Let’s repeat, that is 11-17 years of training. Let us emphasize what goes on in that training. When you look up differences, organizations ensconce the number of years, the accreditation, will play up that non-physician personnel saves money, they fill a need, they are just as good, let’s repeat, they are just as good. However, the difference lies in the training. In medical school, there is weeding so only the most strong-willed  progress to residency. Hours and hours of studying occurs before becoming an M.D. or D.O. Students learn pathology, physiology, pharmacology, anatomy, surgery. These are subjects that are wide in breadth and intense which are difficult to even cram in 4 years. Then, there is residency. There is absolutely nothing on earth comparable to the extreme depth of residency training of physicians, absolutely nothing. Internship is spent learning generalities of a wide variety of general subjects. Residents are involved in codes, rotate in the ER, rotate in internal medicine, attend daily conferences, day in day out, day in day out, day in day out. Residency entails 90-hour weeks in some specialties and those who trained before 2002. Residents take detailed histories seeing patients, formulating a diagnosis, seeing patients in the ER, the ICU, and out-patient settings. Patients are presented every single day to a senior attending who have more breadth and knowledge as residents learn from their expertise. Nights are spent at work so that the progression of disease processes and management is understood. One makes split second life-changing decisions while gradually building responsibility. The craft is finely honed daily in the 3-6 years of residency training so that physicians are completely confident to enter practice or further training in fellowship, which is another 1-3 years. This will never ever be equivalent to any other type of training on earth regardless of the profession. This is what makes a physician a physician. That knowledge and skill set is irreplaceable unless the same training is undergone. Patients can tell a difference, physicians can tell a difference. It doesn’t matter how many other years other non-physician personnel may have trained or shadowed in the hospital, it will never be anywhere equivalent to the medical studies, residency, fellowship training, board examinations and most especially the vast wealth of experience that makes a physician a physician.

Patients entrust their health, their well-being and even their states of mind to their physicians. Physicians train not only for their specialties and subspecialties but they have the unique skill set to recognize subtle symptoms giving rise to other possibly devastating diseases. They are exposed to a myriad of diseases and are able to respond to chronic and to some of the most acute issues that encompass a vast fund of knowledge one can only derive from years of study and training. This can only come with the extensive training and experience which well-trained physicians have. When this perfect system and bond of a well-trained physician and a patient is broken, the system collapses. Physicians are terminated all over the country by administrators when they speak up about the diminishing quality of care when the less trained personnel deliver care or when denouncing profit over patient. Rather than addressing the problem at its roots, we place bandaids.

How did we come to this? A brief background of the demise of medicine

Once upon a time, private practices flourished. Physicians followed their own patients in the hospital setting. There were no teams. The relationship was between doctor and patient.

Recently, hospitalists cared for patients  disrupting the continuity of care which has evolved into a team. All the patient knows is that many people in white coats were seen and the doctor’s name is not remembered. Fast forward to the future, solo private practices are as scarce as the dinosaurs that ruled the earth. Pressured by time-consuming requirements of health insurances, practices are increasingly sold to hospital corporations. Medical practices are disrupted and absorbed into larger healthcare systems. Patients are computerized files followed by everybody without a medical degree who are called doctors, practitioners and other misleading terms. This allows patients to believe they are still cared by medically qualified fully licensed physicians. Or even worse yet, we are now all called providers or healthcare providers to even the playing field of titles. Many different skill sets hide behind this title, a title coined by other sources so that everyone is deceptively equally skilled. Physicians should feel insulted when they are called provider. There are many campaigns that champion this course, advocating that it allows greater access to care and that rural places have no physicians. But the bottom line is the bottom line. It’s all about money and hiring the most economic labor for the most valuable skill set required. It has happened at the primary care level and anesthesiology level. They’ll soon be coming for the jobs of radiologists and surgeons if artificial intelligence and robotic technology do not intercede.

Health insurances and drug companies are the dominant forces having an illicit affair with each other, while we are the bystanders that are profoundly affected by their decisions. Physicians contract with insurance companies and render services to patients.  Coding is the norm where a multitude of questions are answered and documented so physicians are reimbursed. This is why burnout is rampant and valuable face-to-face time is replaced. This works superbly for insurance companies. Businessmen rise in ranks dictating the quality of care.

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Care is impeded by requirements of insurance companies. Physicians have to fight insurance companies in order to obtain an MRI of the brain for a patient they are worried might have a tumor. They undergo a process called a peer-to-peer review. A physician who is usually not a specialist employed by the insurance company reviews the clinician’s notes and determines whether the test will be covered. It might simple but not when it can take 15-20 minutes for one test. Multiply that by the number of tests that is reviewed. This is a wastage of valuable patient-physician time. This is a source of infinite frustration to physicians but insurances dictate the quality of care because they hold the purse strings for healthcare, controlling who gets the test. If it is denied then the physician and staff waste even more time appealing. If an MRI is ordered for a tumor, this may delay diagnosis and care where time is of the essence. Insurance companies obfuscate in hopes that tests or certain medications are not pursued, saving them money.

Patients who need specialists have to see their primary care doctor to get a referral in order to see a specialist which can delay care. Time is exceptionally important in cases such as in patients with oncologist conditions where every crucial day that is delayed in diagnosis may result in greater shortening of life expectancy.

Physicians are subconsciously dictated into referring within network because it is covered by health insurance even if a more qualified physician is a few feet away but may be out of the network. This boosts profitability within the insurance companies.

Appointments are reduced to 10 minute slots. Yes, they can be extended but physicians need to pay overhead, malpractice insurance, staff wages and any school debt. It is not financially feasible to see 8 patients in one day. Patients only see that their doctors are spending more time on the computer and have less eye contact. They feel unheard and unnoticed. They do not understand the pressures physician must face or that the system has transformed the quality of medicine. Physicians are at risk of an increasing number of errors because they work at a higher and higher levels. Those who supervise non-physician personnel oversee the care of up to 60 patients a day. These are worse conditions than residency because physicians assume all liability.

Where did things go very wrong?

One of the pivotal moments occurred when physician assistants and nurse practitioners assumed larger responsibilities, at times well beyond their training can handle. They are paid less than physicians and have trained substantially less than physicians yet work under the same conditions, giving medical advice, and writing prescriptions. They manage the care of a patient that was once the privilege of a physician. When I previously worked in New York City, I had the pleasure of working with some wonderful Physician Assistants and Nurse Practioners under neurosurgery. They called my neurological services when needed. They took care of the neurosurgical care of patients on the floor under the supervision of the neurosurgeon. But they knew their lane and worked under such. It was a well-oiled machine where everybody stayed in their lane. The quality of care was superb.  Fast forward nearly over a decade, PA’s and NP’s manage complex patients on their own with a physician type role. The job description is completely different and the training is ill-fitting to such a role. This is where the problem lies.

Once upon a time, there were military corpsmen working side by side with surgeons during the Vietnam war. They checked blood pressures, started IV lines, recognized and triaged patients.  They developed finely honed, valuable clinical skills. When the Vietnam war ended there were many medically skilled corpsmen whose skills would be wasted which how the position medical assistant was born. These jobs were created as a complementary position in aiding in healthcare. The positions of a PA and NP are similar, working as a complementary skill set in healthcare. They have a place in healthcare. But they were never originally intended to replace the extensive knowledge and skillset and training of a physician. To do so only invites a markedly different and not necessarily more superior quality of healthcare.

There are now nurse practitioners pushing for independent practice unsupervised to dole medical advice. They are a boon for any business administrator in medicine. In the hospital setting, one doctor could be supervising 5 nurse practitioners, therefore less financial burden on the part of hospitals. Liability is less expensive for hospitals because instead of 6 doctors they can pay for one while the doctor assumes more responsibility and all liability. The minute a physician speaks up about the quality of care they are dismissed quietly and either terminated or forced to resign. Many physicians do not come forward with their observations due to fear of retaliation or retribution. Many go on quietly working in other practices with the incident never to be spoken of again. They are gaslighted thinking they somehow did wrong by whistleblowing on the corruption of medicine. Very few come forward with their stories which they hide, feeling shamed and devastated.

How physicians and patients are fleeced alive

There are now many organizations working for physician recredentialing and maintenance of certification but the bottom line is profitability. Physicians supply the goods. Physician organizations work in cahoots with these other systems. While it is supposedly prestigious to be a member of a professional organization, everything is intertwined with money being the center. MOC (maintenance of certification) is a requirement entailing large fees in the hundreds annually and in the thousands over a decade. In Neurology, recertification and MOC over is a grand total of $23,580 over 30 years including examinations or $377,727,280 for more than 16,000 neurologists. This is highway robbery and doctors in every specialty are skinned alive. A physician cannot work in a hospital unless certified. A physician cannot be reimbursed by insurances unless you are certified. What was once voluntary is now coercion in order to drain from physicians. One of the very few non-corrupted professional pro-doctor organizations is the American Association of Physicians and Surgeons who are truly physician and patient advocates. The PPP or group for Physicians for Patient Protection is a pro-patient and pro-physician group that implements proactive work. Other grassroots physician-led actions are from members of the group Physicians Working Together.

Health insurances are misnomers. The health premiums run into the hundreds and thousands a month which do not kick in unless you completely paid off your deductible. A deductible is a deceptive term where one must shoulder thousands of dollars before the insurance coverage is activated. This is an incredibly profitable business for insurance companies because there is no return in investment until one is short several thousands of dollars. Healthcare is a universally needed commodity. Supply and demand dictates that the higher the necessity the more someone is willing to pay for that need, it’s sheer unadulterated business genius. Insurance companies work in close collaboration with pharmacies, drug companies which is why only certain drugs are approved. It steers that patient towards obtaining the drug with which the insurance company works with. There are other nuances about new medications, pharmaceutical drug company driven research data, connection of pharmacies, drugs and health insurances but that’s a whole different article that can be expounded at length.

It is 2018, medicine is now an extremely corrupted business of profit over patient.

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One doctor decides to take a stand for patient care

However, one physician did decide to take a stand for patient care. http://padailypost.com/2018/03/20/medical-group-goes-doctor-1-4-million-legal-fees/ Diana Blum is a neurologist who worked in a medical practice in Palo Alto in 2009. When she became a shareholder and attended business meetings, she became more cognizant of the business dealings of the group. Some examples were reported to include not referring out of network, not using drug samples and other practices that increases profitability from a business aspect. When she commented on the negative impact on patient care she was labelled a “non-team-player,” “disruptor” and using “inappropriate comments.” She was reported as offered 3 options (1) resign to avoid negative letters of recommendation, (2) be terminated or (3) bring a claim or expose to the media knowing she might never work in that area again. She was reported as placed under PIP or performance improvement plan despite having some of the highest ratings in satisfaction by patients. She opted to resign under coercion. At one point, she consulted on one patient with reported negative impact from these types of practices and decided to take a stand. Many of the relevant facts were suppressed because the judge reportedly thought it might bias the jury. The judge was reported as siding with the other side as to who owes legal fees. There are still many details that Dr. Blum is not at the liberty of declaring since an appeal is ongoing. She reports there are many physicians in the same company with similar observations and pressures but cannot speak due to fear of retaliation and repercussions. This information was shared with her permission.

This marks the crossroads of medicine. After all the extensive documentation for electronic medical records, the shortening of the face-to-face time physicians have with their patients, the quiet rampant replacement of physicians with nurse practitioners and physician assistants where in some states they are allowed to work independently, this is one incident that must not be a small blip on the news, that must not be allowed to fade. It signifies a very important turning point in the standard of care.

It can easily be sensationalized or demonized but this sets the precedence of things to come. It signifies that a physician who advocates for patient care invites termination. If one brings claims against administration, the corporate office has an unending supply of legal arsenal to retaliate against that physician. This has to be one of the lowest points in medicine. This incident is of utmost importance because it sends a chilling message that essentially signals the suppression of physician voices all over the country. If physicians do not take a stand on behalf of patient care, who will? Physicians must be both physician and patient advocates. Nobody cares about physician burnout except physicians. It is of no consequence to anybody else if patients see less of their doctors except to physicians and patients. Both physicians and patients have been on the losing team these past few decades. We need to take back medicine or the only ones who will lose are the very ones it is supposed to serve.

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How can we change the system?

Both physicians and patients need to be their own advocates. Patients must demand to see a physician, not non-medical doctor personnel and have a right to see their physician with whom they have the patient-doctor relationship. Other options are to look into direct primary care and take on catastrophic insurance. This bypasses the monthly costly fees to insurance companies. Physicians involved in direct primary care tend to have access to the lowest rates of medications and can direct patients to less costly outlets. Physicians in private practice and direct primary care have access and knowledge of companies with imaging studies with the most economic rates. Instead of a $3000 MRI deducted from the high deductibles paid out-of-pocket, a wholesale type price straight from the company can be $300. Patients need to be their own advocates by taking care of their health. Everything is interconnected, including the fast food industry, the companies that manufacture processed food, the drug companies, the insurance companies, and the health industry. Everything is big business. When people are chronically ill related to a lifestyle of unhealthy food they need medicine, they need healthcare. It’s an unending profit cycle. Each business feeds into each business. It’s a merry-go-round of profits. Healthy people do not need to see physicians. Prevention is key to keeping the doctor away. Fewer patients mean less shortage which means better quality care from physicians.

Physicians do not need to hang their heads low accepting the workload they are given. There are other options including direct primary care, entering private practice, and deleting insurance companies. Speaking up and raising awareness of these issues should not be discounted. Many physicians are resigned to the fate of medicine but it does not have to be that way. There are physician activists who are well adept and fighting the worthy cause through legislation, including Dr. Westby Fisher who is working to fight MOC. This includes a recent success story of Dr. Craig Wax winning the battle along with 3 other doctors untying professional membership from board certification. There are physician advocates raising awareness of the exorbitant pricing of medications and kickbacks such as that seen in the work of Dr. Marion Mass. Officials have taken note. Physician writers who are well-connected can raise awareness of these current conditions. If you see something say something. Physicians should demand they be called Doctor and Physician not provider, not health care professional, not health care provider. It is an insult to your nearly 11-17 years of training to be called anything other than that. We are physicians who studied to take care of patients to the best of our ability.  It is because of our very complacency and the burgeoning work requirements which have caused these current issues. Nobody else will extricate physicians and patients from these predicaments except ourselves. One day everybody will be a patient, if healthcare is worrisome now, its deterioration will only continue to worsen. The next generation will not even understand what excellent healthcare is because they would have never experienced it which is very sad.

It is easy to be complacent but one day every single one of us will be affected whether at work or at the doctor’s office. When someone’s mother with a devastating disease is cared for by a physician assistant who knows nothing about that patient and has to step outside 4 times to check on records and cannot answer the most important questions, one knows it is time to make a change for the better. It is troubling to say the least when you see a medical office plaque for subspecialty with 16 doctors in white coats caring for the sickest group, when on closer inspection 8 of them are nurse practitioners and physician assistants. In a few years time, there will be fewer with M.D.’s and D.O.’s after their names. One day there will be one licensed physician handling a whole department on non-physician staff.

As I leave my business cards with doctors offices, I am shocked to discover that some practices have non-physicians who are 1/2 the staff on their shingle, especially hospital practices. One day it will be one doctor and the rest non-physicians. Is this really the way we want medicine to become? Physicians are leaving medicine by the droves and are fed up with the state. Others feel powerless and feel that this is their only recourse bogged down by huge loans and personal responsibilities.

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Call to action

Medicine has essentially become a business, an industry, profiting from physicians and patients, employing the least trained personnel to replace and step into their shoes and depriving patients of quality time and care they deserve. In a few years, medicine will become a shell of what it used to be, it will only deteriorate further if nothing is done now. In watching idly continuing about with our business, we are complicit with its decline. If a physician such as Dr. Blum cannot even fight the good fight for patient care and cannot reason that the ongoing healthcare policies are detrimental only to be suppressed and devastated for speaking up, then the rest of us are doomed.

One of the basic tenets of serving as a physician is “primum non nocere,” first, do no harm. To stay silent on these issues grossly impacts patients in a negative manner. But how do we advocate for patients when we are silenced and censored? Dr. Blum is devastated and suppressed for advocating for good patient care. She is the sacrificial lamb in standing up for care. It strikes a chord in many physicians because this is why we chose this profession and trained hard for it. We cannot let medicine be ruined. We rise above it. If we can soldier through 90-hour work weeks during intense training which no sane person would want to experience, why should we let non-physician administrators dictate how we practice or decide that we make inappropriate comments. It is every bit of convolution. If a stand is not taken now when will this descent end?

Medicine is in shambles today because we are complicit and enabled this to happen, perhaps not by choice but by inaction. All the wellness programs in the world will not reverse the underlying cause of the dilemma. The quandary is that healthcare is reduced to a masterful game of production and profit, the pawns are patients and physicians.

We must actively take ownership of our responsibility to our patients, pick up the shards and rebuild the patient-centered system it is supposed to be. We can do this, every single one of us by not tolerating these conditions by saying no to the current state of affairs. Some details have been outlined. By not enabling the way medicine is practiced we can make a change. By giving our patients the best of ourselves and not just snippets of time resulting in a gross overload of work we are not doing a justice towards our responsibility towards our patients or ourselves.

Discussing it does not work. But if every single one of us changes our work habits maybe even our work by doing DPC or something similar we take back medicine so we practice how it is supposed to be and not under the restrictive conditions of a profit-driven insurance company. When you’ve practiced under both conditions you see a huge difference. The horse is already out of the barn. But who else will care enough to fix this mess and make changes, nobody else but us.

Primum non nocere, first, do no harm. This is our calling, this is our truth.

Virginia Thornley, M.D. is a neurologist who writes at https://neurologybuzz.com/

@VThornleyMD

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Tic

Cannabinoids: pathways and role in the management of motor tics

Virginia Thornley, M.D., Neurologist, Epileptologist

July 16, 2018

@VThornleyMD

https://neurologybuzz.com/

Introduction

As medical marijuana emerges from the caves of obscurity in treating illnesses, physicians are at the forefront of rediscovering ailments that can be treated by medical cannabis. While most traditional scientists and trained clinicians do not think highly of anecdotal research, patients in clinical practice are the best parameters in judging whether a medication is working or not. Oftentimes, even with the best research, clinical practice conveys side effects that were never found during the short period of time of the study. Additionally, as hundreds of thousands of patients start using a new product it is only then one can observe the true efficacy and safety profile which accounts for why research does not always correlate with clinical practice.

Sometimes, one comes across a medication where certain other symptoms may be alleviated not listed on the indications. As a growing number of patients are  recommended medical cannabis, they are presenting with a variety of symptoms that are incidentally relieved.

Background of endacannabinoids and relationship to areas in the brain subserving movement

One of the areas where the brain is rich in endocannabinoid receptors CB1 and CB2 receptors are in the basal ganglia which subserves the function of movement modulation. There likely exists a role of endogenous cannabinoids in the regulation of movement given its abundance in this area. The CB1 receptors are found in the striatum and caudate nucleus which are rich in GABA-ergic neurons, and pre-terminals of the internal and external globus pallidus, and substantia nigra. They are found in the glutamatergic pathways within the cortical systems and in the subthalamic nucleus (1).

The endocannabinoid system appears to inhibit glutamatergic pathways and increases GABAergic activity in the basal ganglia. It affects the dopaminergic pathway (2). It is speculated that the endocannabinoids may play a role in modulating the various neurotransmitter systems. While large clinical randomized controlled clinical trials may be lacking there is evidence that cannabinoids may reduce the clinical manifestations of motor tics (2).

Review of case studies and case series

There is a paucity of clinical trials studying the role of cannabis in movement disorders. Most of the data is from pre-clinical studies or case reports. Clinical research undoubtedly has been stunted given the scheduling of the agent under a schedule I category and other related factors.

In a small study of 12 patients, tetrahydrocannabinol was studied to determine effectiveness in treatment of tics(3). The Tourette Syndrome Symptom List (TSSL) was utilized for self-evaluations by patients. The examiners used the Yale Global Tic Severity List, Shapiro Tourette Syndrome Severity Scale for rating the severity of tics. A randomized controlled clinical trial was carried out. Those in the group where delta-9-tetrahydrocannabinol showed improvement compared to the placebo control group. There was great improvement using the TSSL with a p=0.15. Significant improvement found with complex motor tics using examiner ratings. Simple and vocal tics showed improvement (3).

In a case series of 19 patients, there were 60% who had much less motor tics after treatment with cannabinoids. There were 18 patients who felt they significantly improved (4).

In summary

The fact that the endocannabinoid system on which cannabinoids work is widely found within the basal ganglia which modulates fine movement correlates the function it has with modulation of movement.

While the scarcity of clinical trials is evident, cannabinoids continue to be used in clinical practice with some modicum of success for treatment of motor tics.

https://neurologybuzz.com/

Introduction/Disclaimer

About

References

  1. Koppel, B. Cannabis in the treatment of dystonia, dyskinesias, and tics. Neurotherapeutics. 2015, Oct. 12(4):788-792
  2. Muller-Vahl, K.R., Kolbe, H., Schneider, U., Emrich, H.M. Cannabis in movement disorders. Forsch Komplementarmed. 1999. Oct. 6 Suppl 3:23-27.
  3. Muller-Vahl, K.R., Schneider, U., Koblenz, A., Jobges, M., Kolbe, H., Daldrup, T., Emrich, H.M. Treatment of Touterret’s syndrome with delta 9-tetrahydrocannabinol (THC) a randomized crossover trial. Pharmacopsychiatry. 2002, Mar. 35(2):57-61
  4. Abi-Jaoude, E., Chen, L., Cheung, P., Bhirkram, T., Sandor, P. J. Neuropsychiatry Clin Neurosci. 2017 29(4):391-400
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Alzheimer's disease

Cannabinoids: pre-clinical studies on anti-inflammatory and neuroprotective effects in Alzheimer’s disease

 

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

https://neurologybuzz.com/

June 25, 2018

Introduction

Alzheimer’s disease is not a natural progression of senescence. It is a neurological disorder involving deposition of beta amyloid peptides in senile plaques and accumulation of amyloid precursor proteins within the cerebrum particularly in areas affecting memory and cognition. Current pharmaceutic agents at best can only slow the progression of this disorder. There is no cure. Because it not a devastating illness in that it does not decrease the longevity per se, nonetheless, it is devastating to the patient and family members around him or her.

With the advent of cannabinoids into the pharmaceutic fold, attention is turning towards medical value outside its well-known repertory including anti-inflammatory and neuroprotective properties. Can cannabinoids slow the inflammatory process that is involved in this neurodegenerative condition? This seeks to explore mechanisms by which cannabinoids may play a role in ameliorating the clinical effects seen in Alzheimer’s disease.

Endocannabinoid system

As an overview, the endocannabinoids system is found naturally within the body consisting of endocannabinoids, enzymes and receptors. There are 2 receptors the CB1 receptor which is concentrated in the nervous system and found to a lesser extent in other organ systems and the CB2 receptor which is found mostly in the immune system and in other systems.  Anandamide is an endocannabinoid that exerts its actions on the CB1 receptor, while di-arachidonoylglycerol has a low affinity for the CB1 receptor and interacts with the TPRV or transient receptor potential channels of the vanilloid subtype and the G-coupled receptor family.

Within the cannabis sativa plant are 2 most well-studied phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The CB1 receptor is where delta-9-tetrahydrocannabinol (THC), a mimetic of Anandamide, interacts and can cause psychoactive effects. Cannabidiol is a mimetic of di-arachidonoylglyerol with a lower affinity to the CB1 receptor where 100 times the amount of CBD is required to achieve the same psychoactivity as THC. When CBD and THC are combined there are less side effects since the CBD acts as a non-competitive allosteric modulator at the  CB1 receptor. When the 2 are combined there is an effect that is increased together compared to when each cannabinoid is taken alone, where the effect is significantly much different. The presence of CBD offsets side effects of THC. Common side effects include agitation, hyperactivity and paranoia.

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Mechanisms

Senile plaques are found to express CB1 and CB2 receptors within the brain in addition to microglial activation markers. The neurons are rich in CB1 receptors but seem to be greatly reduced in microglial activated areas. CB1 receptor expression and G-related coupled protein are reduced in brains with Alzheimer’s disease. Nitration of proteins are enhanced especially in CB1 and CB2 proteins in Alzheimer’s diseased brains. Adding synthetic cannabinoid WIN55-212-2 to rats caused an inhibition of microglial activation and neuron marker loss. Cannabinoids were found to ameliorate neurotoxicity caused by microglial activation (1).

Another study demonstrates the role of cannabinoids on inflammation in the mouse model using synthetic cannabinoids JWH-133 and WIN55.212-2. Cognition and inflammation were studied. FDG uptake on PET scan  was used to assess areas of metabolic uptake. The amyloid precursor protein mice showed poor object recognition. After administration of the JWH compound, cognitive impairments were reversed. There was reduced FDG uptake in the hippocampal areas. No changes were seen using WIN55.212-2. Beta amyloid proteins were significantly reduced in the mice models when cannabinoids were applied. Microglia was elevated in the APP mice which was reduced after cannabinoid administration (2).

In another mouse study, CB2 receptors were at a low level found in the neurons of unmanipulated mice whereas there was a noted increase in the CB2 receptors in mice that underwent chronic inflammation in the microglia surrounding plaques. This suggests that there is an upregulation of CB2 receptors in the presence of pathological inflammation. This may be a potential target in therapeutic agents in the future (3).

In summary

These pre-clinical studies demonstrate a neuroprotective and anti-inflammatory role of cannabinoids on Alzheimer’s disease. The CB2 appears to be upregulated around activated microglial cells around plaques implying a possible therapeutic target for future treatments. While pre-clinical studies are not human trials, elucidating these mechanisms may play a role in the future therapeutic benefits of cannabinoids on Alzheimer’s disease.

https://neurologybuzz.com/
Introduction/Disclaimer

About

 

References

  1. Ramirez, B.G., Blazquez, C., del Pulgar, T.G., Guzman, M., de Ceballos, M.L. Prevention of Alzheimer’s disease pathologyby cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25:1904-13
  2. Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G.,  Cuadrado, A., de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflam. 2012, 9:8
  3. Lopez, A., Aparicio, N., Pazos, M.R., Grande, M.T., Barredo-Manso, M.A., Benito-Cuesta, I., Vazquez, C., Amores, M., Ruiz-Perez, G., Garcia-Garcia, E., Beatka, M., Tolon, R.M., Dittel, B.N., Hillard, C.J., Romero, J. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflam. 2018, May, 15:158
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Cancer research and cannabinoids

Cannabinoids: a review on pre-clinical studies on anti-angiogenesis, apoptosis and reduction of MMP-2 expression inhibiting cancer cell growth

Virginia Thornley, M.D., Neurologist, Epileptologist

June 24, 2018

@VThornleyMD

https://neurologybuzz.com/

Introduction

The surge of recognition of the medical significance of the cannabis sativa can no longer be ignored. Frustrated with the futility of current pharmaceutic agents, their associated side effects and costs, there is a growing tendency for more natriceutic measures of therapy. Shunned by physicians and by the public, there is a growing clamoring of medical marijuana advocates for its use. There is only a small proportion of physicians qualified to recommend this agent. Prescribing is federally illegal as it is still classified as category I drug. In the state of Florida alone, as of June 2018, out of 75,000 licensed physicians, only 2100 are qualified to recommend it or 2%. Long known for the stigma of its recreational value, its foothold in the medical community is slow-going. Most of the public associates the plant with unseemly, clandestine purposes. The federal law against it stands steadfast, with legislation moving at a molasses pace, even while recognized by state laws. These variables account for the great difficulty procuring this agent which is not only organic and all natural but medical in nature.

However, there is great interest in this plant. The pre-clinical data shows promise but more larger clinical trials are still needed. It seems to be far reaching in its effects and because it is still not well-studied, the vast number of purposes is still largely unknown.

Interest turns towards any anti-neoplastic application it might have. Pre-clinical data has shown some promise, although it may not always translate into human results. The scientific data points towards some benefits in the neoplastic process.

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Endocannabinoid system

In an overview of the endocannabinoid system, there are 2 cannabinoid receptors, CB1 and CB2. The CB1 receptor is abundant in the nervous system and found to a lesser extent in other systems. It is through this receptor that psychoactive properties are activated. The CB2 receptor is found largely in the immune system. Anandamide interacts with the CB1 receptor, of which delta-9-tetrahydrocannabnol is a pharmacomimetic. While 2-AG or di-arachidonoylglycerol is a low affinity agonist at the CB1 receptor. Cannabidiol (CBD)is a mimetic of 2-AG, where 100 times the amount of CBD is needed to get the same effect as THC. It has a full ligand effect on the CB2 receptor. The CB1 receptor is a G-protein coupled receptor. Cannabidiol interacts with the TPRV transient receptor potential channel and the GPR or G-protein receptor family. Expression of the cannabinoid receptors are most notable in areas engaged with memory, motor, learning, emotions and endocrine functions.

Endocannabinoids and the role in cancer

The beneficial effects of cannabinoids on symptoms pertaining to neoplasms such as anorexia, nausea and pain are well-known. Investigations turn towards any effect on the actual neoplastic process.

An upregulation of CB receptors are found in high volume in cancerous processes. The enzymes involved are also at high levels. This suggests that the endocannabinoid system may play a role in the neoplastic process. The frequency of the receptors and amount of enzymes may correlate with the aggressiveness of the type of cancer. This suggests that the endocannabinoid system may be revved up and play a role in promoting a pro-tumor environment.

Conversely, there are studies suggesting that activation of the cannabinoid system may be anti-tumorigenic. Reduction of tumor growth was observed with a  reduction in the endocannabinoid degrading enzymes(1).

While there are some inconsistencies, overall, the anti-tumorigenic effects appear to be better demonstrated in pre-clinical studies.

Effect on tumor cells

Overall, there are more studies that cannabinoids including phytocannabinoids such as tetrahydrocannabinol and cannabidiol and synthetic cannabinoids such as JWH-017 show anti-tumorigenic effects.

In one study, the CB1 receptors were found to inhibit the anti-metastatic nature of the K562 cell line which acts as a chronic myelogenous leukemia model in the study (2).

In glioblastoma multiforme tumors, CB1 and CB2 receptors are both expressed. Altered expressions of the receptors were thought to correlate with the manifestation of gliomas and glioblastoma multiforme. Cannabinoids are thought to manifest anti-proliferative activity against tumor cells by 2 mechanisms: anti-neogenesis of vasculature and promotion of apoptosis (3). In one study of glioma stem cell-like cells from glioma cell lines and glioblastoma multiforme biopsies, there was demonstration of the presence of CB1 and CB2 receptors. CB receptor activation changed the gene expression that controlled the stem cell multiplication and differentiation. in addition, cannabinoids were found to reduce cells with the biomarker nestin which is a neuroepithelial cell progenitor. Cannabinoid treated stem like cells resulted in more differentiation and reduced expression of nestin which promotes glioma formation (3).

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Cannabinoids were found to reduce angiogenesis by inhibiting the migration of vascular endothelial cells and by stopping the expression of MMP and proangiogenic factor in neoplastic cells (4). By preventing the increased vasculature cell migration, tumor growth is suppressed. With cannabinoids selectively acting on tumor cells, apoptosis is rendered resulting further in the blocking the growth of cancer cells resulting in the reduction in the proliferation of cancer cells (4). This study is significant because cannabinoids might be developed to achieve effect on reducing proliferation of tumor cells.

In a significant mouse model study, cannabinoids were found to reduce the activity of metalloproteinase matrix in glioma like cells. C6.9 and C6.4 glioma cell lines were used which are cannabinoid models showing cannabinoid responsive and resistant responses. Biopsy samples of 2 patients with multiforme glioblastoma were used. The cells were treated with tetrahydrocannabinol, JWH-133 a synthetic cannabinoid with CB2 receptor agonist effects and fumonisin.  MMP was measured. The C6.9 cell line was found to have less tumor cell growth and less MMP-2 expression found on western blot using SDS-PAGE when treated with cannabinoids. It selectively reduced MMP-2, other MMP’s remained the same level. In C6.4 cell lines, tumor growth and level of MMP-2 were not affected. The study demonstrates that cannabinoids inhibit tumor cell growth and lowers MMP-2. MMP-2 is expressed in many different cancer lines especially aggressive activity. While the tumor generation is more complex than this, the study adds significant information about tumor genesis and a role of cannabinoids in suppressing cancer growth (5).

In summary

Cannabinoids can affect the aggressiveness of tumors by inhibiting the vascular neogenesis. In addition in the animal model for gliomas, it is demonstrated to suppress cancer cell growth and the expression of MMP-2 which is associated with many neoplastic cell lines. More studies are needed as the neoplastic process is complex. In addition, pre-clinical studies need to be translated into human studies. Every mechanism elucidated helps towards understand the complex pathophysiology of cancer and potential therapeutic targets.

References

1.Śledziński, P., Zeyland, J., Słomski, R., Nowak., A.  The current state and future perspectives of cannabinoids in cancer biology. Cancer Biology. 2018; 7(30):765-775

2, Gholizadeh, F., Gharehmani, M.H., Aliebrahimi, S., Shadboorestan, A., Ostad, S.N.  Assessment of cannabinoids agonist and antagonist in invasion potential of K562 cancer cells. Iran Biomed. 2018  (epub ahead of print)

3. McAllister SD, Soroceanu L, Desprez P-Y. The antitumor activity of plant-derived non-psychoactive cannabinoids. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2015;10(2):255-267. doi:10.1007/s11481-015-9608-y.

4. Blazquez, C., Casanova, M.L., Planas, A., del Pulgar, T.G., Villanueva, C., Fernandez-Acenero, M.J., Aragones, J., Huffman, J.W., Jorcano, J.L., Guzman, M. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003, Jan., 17(3):529-531

5. Blazquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., Gonzalez-Feria, L., Haro, A., Velasco, G., Guzman, M. Cannabinoids inihibit glioma cell invasion by down regulating matrix metalloproteinase-2 expression. Neuropharmacology. 2008, Jan. 54(1):235-243

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