Virginia Thornley, M.D., Neurologist, Epileptologist
June 17, 2018
Fibromyalgia used to be a condition denoting excessive pain and was previously questionable as there was no testing that could prove or disprove it. Now, the current thought is that it is attributed to hypersensitivity of the nervous system to pain impulses resulting in multiple points of pain in the body.
Endocannabinoid system in pain modulation
The endocannabinoid system is a major chemical neurotransmitter system that has only come to light as to physiology in the last 20 years. The CB1 receptor is found predominantly in the nervous system on which the endogenous endocannabinoid anandamide exerts its effects. The CB2 receptor is found mostly in the immune system on which 2-Arachidonoylglycerol acts. In the nervous system, cannabinoid receptors are seen in the periaqueductal gray area, ventromedial medulla and dorsal horn of the spinal cord which are areas where pain transmission takes place. This suggests that endocannabinoids play a major role in modulation of pain and can impact pain control through manipulation of this system.
Anandamide and and 2-Arachidonoylglycerol are synthesized on demand. It is released immediately after production. 2-AG is formed from a 2 step process. Anandamide has a low affinity to the TPRV1 receptor (2).
1,2-diacylglycerol (DAG) is a precursor or 2-AG which is formed by hydrolysis of membrane phosphoinositides. DAG is hydrolyzed by 2-AG hydrolase to form 2-AG. 2-AG may be stimulated by activation of G protein receptor such as glutamate receptors. It activates both CB1 and CB2 receptors. Cannabidiol which is found in the cannabis sativa plant is a natural mimetic of 2-AG. Endogenous 2-AG is found 170 times more than Anandamide in the brain. Exogenous 2-AG suppresses nociceptive stimulus (2). 2-AG activity is potentiated with natural 2-acylglycerols which enhances the effects which does not happen when used alone. This is an entourage effect found in the brain where the combination of substances give a combined resulting effect which does not occur if used alone (2).
Mechanisms in pain modulation
Cannabinoids were found to reduce nociceptive transmission at the level of the pain c-fiber responses in the spinal dorsal horn.
Randomized controlled trial in fibromyalgia
In one study of 40 patients in a randomized controlled clinical trial, nabilone which is a synthetic cannabinoid was given over a 4 week period. Measures that were evaluated included the visual analog scale for primary outcome and for secondary outcome measure, tender points, secondary outcome measure, Fibromyalgia Impact Questionnaire (FIQ) at weeks 2 and 4 were used. There was statistical difference in treated vs. control groups for pain (P value< 0.02), anxiety (P<0.02 and FIQ (P<0.02). There were more side effects for the treated cohort compared tot he placebo controlled group. This study demonstrates that cannabinoids may be an effective treatment for fibromyalgia (1).
In one paper that reviewed 18 randomized controlled clinical trials of cannabinoids in chronic pain syndromes including fibromyalgia, cannabinoids were found to be an effective type of treatment. Despite the short duration of the trials, pain relief was effective and mild to moderate adverse effects were noted. Larger clinical trials are needed (2).
Virginia Thornley, M.D., Neurologist, Epileptologist
March 24, 2018
Any news outlet you peruse is bound to have mention of the current opioid crisis looming on the horizon. Opioids are commonly prescribed as the last resort for patients with chronic pain who have failed conventional medications, interventional measures such as epidural injections or surgery, non-pharmacologic measures such as physical therapy and even Eastern techniques such as acupuncture. With tolerance a common problem and patients needing higher and higher dosages for pain control because of the properties of opioids, it is little wonder that chronic pain control is difficult to maintain.
The hot topic of debate in many states is the recognition of medical marijuana as a legitimate medication for chronic ailments. However, because of the stigma it has incurred being well-known for its psychoactive properties and widely seen in pop culture in movies with kingpins smoking it for recreation, the medicinal values are often overshadowed and lack of side effects in low doses is easily overlooked.
Not your stereotypical patient and not your direct referral
Patients and even physicians likely have a preconceived notion of who seeks medical marijuana. While chronic pain is top of the list, often times, it is discovered by the hard-working carpenter who discovered it online and found a small scientific article on non-pharmacologic treatments trying to come off sedating pain-relieving medications. It will be the former business owner who lived an enjoyable life being active dancing or the woman afflicted with an autoimmune disorder and has failed every medication under the sun. Many times patients come in not because they want to feel good but because it is their last resort and they’ve exhausted every treatment option known to mankind. They dislike the side effects of the strong painkillers such as opioids and just want the pain to stop and live a normal life. It is amazing how indirectly patients hear about the wonders of medical marijuana, it will usually be a neighbor who swears by it, or somebody’s friend who mentions it out of the blue. Oftentimes, it is by word of mouth since the few physicians interested in recommending it are very reluctant to advertise with good reason.
Mechanisms of cannabidiol and tetrahydrocannabinol
Medical marijuana has been used since B.C. period for thousands of years as a medication. It was incorporated into the pharmacopeia of American medicine in the 1850’s until it was banned in the 1930’s. It regained popularity and notoriety as a recreational substance. However, more and more patients are turning towards this now alternative medication after years of frustration towards the ineffectiveness and adverse effects of conventional medications. The endocannabinoid pathway is found inherently in the system and is responsible for the runner’s high that people get after a vigorous run or after exercising and gives the sense of well-being. The CB1 receptor is found most abundantly in the central nervous system which is likely why many neurological conditions are found to benefit from its use. The CB2 receptor is most commonly found in the immune system. As more research is pursued, there are CB receptors found diffusely throughout many organ systems. Cannabidiol weakly interacts with the CB1 receptor. It takes at least 100 times cannabidiol to attain the same intoxication one gets with tetrahydrocannabinol, the substance which is more popular and found in the marijuana joints people smoke to obtain euphoria. THC at low concentrations is effective in treating many different medical conditions. It must be used in conjunction with CBD so that side effects are offset. Cannabidiol has no intoxication while low doses of THC does not give euphoria one associates with this drug. There is no tolerance.
Scientific evidence cannabidiol and tetrahydrocannabinol work in chronic pain and other medical diseases
In animal studies, it is well known to reduce seizures by inhibiting the excitation within the hippocampus of the brain where seizures are commonly propagated (http://www.pnas.org/content/early/2017/09/26/1711351114).There are many clinical trials in humans attesting its efficacy at controlling seizures effectively. CB1 receptors appear to be increased in many neurological disorders which implies it is a compensatory mechanism for diseases. In Parkinson’s disease, there are increased CB1 receptors which may help with the reduced dopamine commonly found in Parkinson’s disease. 9tetrahydrocannabinol was found to lower intraocular pressure in glaucoma in rabbits (https://www.ncbi.nlm.nih.gov/pubmed/6329602). Sativex is a combination of THC:CBD which reduces spasms in patients with multiple sclerosis and has been available in Europe for several years now with very little side effects http://jnnp.bmj.com/content/87/9/944. There is extensive evidence in both animal and human models that it works in chronic pain (https://www.ncbi.nlm.nih.gov/pubmed/26830780). Many diseases are being evaluated for mechanisms on which CBD and THC may exert its effects. It has been found to have anti-oxidant and anti-inflammatory properties which are important mechanisms by which many diseases cause pathology. In cancer cell cultures, it has been found to reduce proliferation of tumor cells in urologic cancer and reduce the pro-inflammatory states that are necessary for metastatic conditions (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434502/).CBD interacts with the 5HT1 receptor where many anti-depressants and anxiolytic medications exert their effects, making CBD an effective anxiolytic. It works to stimulate appetite and is commonly used by patients with cancer for anorexia and end-stage cancer pain.
In summary, cannabidiol and tetrahydrocannabinol are effective medications in treating pain from many chronic illnesses and is not reserved for patients with terminal illness. Despite the reticence of physicians, Congress and even patients, there is overwhelming evidence that cannabidiol and tetrahydrocannabinol are effective in many different diseases, although in some conditions there’s a long way to go from preclinical data to human trials. It is fairly clear in many disease states, medical marijuana is significantly effective. There is no tolerance and may be an effective treatment for patients with chronic pain. CBD by itself has no euphoric properties and low concentrations of THC do not give intoxicating psychoactive effects. These are 2 alternatives that may provide relief and solution to the growing epidemic of the opioid crisis.
Virginia Thornley, M.D. Neurologist, Epileptologist
The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010. Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.
How it works–the nitty gritty
Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly. Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated. CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.
Current legal state of affairs
Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law. In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store. Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.
In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.
Virginia Thornley, M.D., Neurologist, Epileptologist
March 11, 2018
A patient comes to you asking “Doc, my seizures are getting worse, I really hate the side effects of my medications, I really want to go a different route. Have you heard about medical marijuana?” You start sweating profusely, fidgeting in your seat, thinking of every single reason why not to recommend it and come up with the standard response, “uh, well, I’m not qualified to recommend it and it’s not FDA approved, plus we don’t really know much about it there could be so many side effects.” And then we have the oldie but goodie response, “there’s not enough large randomized control trials to recommend it.” This scene plays 100,000 times over if not a million times over in physician offices across the country. Patients who are disillusioned with adverse effects of medications are looking towards alternative therapy. As surprising as it sounds, patients with chronic pain do not want to get intoxicated by opioids. In fact, some want to be tapered off of them or refuse them all together. Patients with end-stage cancer at the terminal stage of their lives wish to live a comfortable and humane existence without the need for more chemotherapeutic medications or pain medications that consistently make them feel like a zombie. While other patients with epilepsy may be on 4 different anti-epileptic agents and can no longer function or have a good quality of life because of side effects. There are two sides to every coin.
Why you should be educated on cannabidiol and THC use in medical conditions
If patients do not get their answers from their trusted physicians who they trust with their well-being, their health, the temples of their souls, they will go to great lengths in procuring this knowledge. This is via various sites on the internet some of the dubious nature others are from high quality companies that have been in business even before this seeming treatment fad started. Or, the information may be obtained from their brother-in-law’s friend’s hair stylist who is now pain-free after going through a long course of pain medications including ablative treatments, physical therapy, and acupuncture and has a physician who does recommend it. Like it or not, cannabidiol and tetrahydrocannabinol are alternative treatment options and are gaining more and more traction. To ignore it is to be complacent with the changing direction and landscape of medicine. As patients become more and more disillusioned by the limitation of conventional treatments, attention is directed towards alternative regimens. It is not just for the yoga-practicing patient looking for more natural methods, one sees the sweet 83-year-old gentleman who must be someone’s grandfather with the chronic hip pain of 50 years who have failed opioids and is simply looking for pain relief.
Is there any evidence that it works?
The endocannabinoid pathway is found naturally in the system. It is responsible for the runner’s sense of wellbeing one gets after a 5-mile run and the pleasant mood you get after a 1-hour work-out with Zumba. There are 2 receptors in the system CB1 receptor which has the highest number of brain cells and the CB2 receptor which is found predominantly in the immune system. There are 2 common cannabinoids cannabidiol and tetrahydrocannabinol which exert various medical effects. Cannabidiol (CBD) has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria that one gets from tetrahydrocannabinol, the bane of every ER physician. Unfortunately, the side effects of euphoria of THC have preceded its popularity as a medical product. Little do we know it was once used for hundreds of years as a medication before the psychoactive properties were exploited for recreational purposes. In urologic culture cell lines, it is found that cannabinoids may reduce proliferation of cancer cells and reduce the pro-inflammatory microenvironment that is necessary for metastatic conditions (1). Human studies are still needed to determine a reduction in tumor loads. THC receptors are found in retinal cells and may be found to reduce intraocular pressure in glaucoma (5, 6). Cannabidiol is found to bind to the 5HT1 receptor which reduces anxiety. THC has been well-established in the mouse model to promote the inhibitory control of excitatory pathways in the hippocampus, where seizures commonly arise (8). There is an increase in CB1 receptors after prolonged seizures suggesting a compensatory response. It has been used in combination and found in several randomized control trials to reduce the frequency of seizures by as much as 36% in medically refractory patients (2). It is well-established that cannabinoids reduce pain refractory to conventional medications (3). It has been found in bench research to be an antioxidant and have anti-inflammatory properties (4, 7). Some studies cite side effects of somnolence, nausea, dysphoria, however, it is not clear what was the quality of cannabinoids or dosages were used. At high doses, while THC can reduce pain it may also result in side effects, which is why it is usually used in combination with CBD which ameliorates the side effects of THC. In addition, cannabidiol by itself has no euphoria and it takes 100 times the amount to achieve intoxication seen with THC use. Synthetic products will have more side effects than products that are organic meaning only of natural materials.
Given the huge amount of evidence in several different medical conditions (3), the results should overwhelmingly be towards a push in using cannabinoids more frequently. However, because of the cynicism of the public, physicians even of patients, who have been exposed more frequently to the harmful psychoactive side effects, the benefits are far overshadowed. More clinical randomized controlled trials are needed. Most literature cites small numbers of patients enrolled in studies or review multiple medical centers where the conditions are not uniform. In addition, some of the patients that would benefit the most are the least in numbers such as those with rare neurological conditions such as Dravet syndrome or Lennox-Gastuat syndrome.
As it still stands, many states still do not recognize the medicinal value of cannabidiol or tetrahydrocannabinol. In some states, medical physicians are not allowed to recommend it and put themselves at risk for FBI questioning in even suggesting its use. It is not uncommon for patients to move states or order from other states or countries to procure this liquid gold that is supposed to work wonders. Only time will tell if this is a passing fad and if there are long-standing side effects, however, as of current standing, medical marijuana is here to stay. As far as the literature goes, there are beneficial results but it is a cautionary tale as more studies in large human trials are still needed. As with any new preclinical data, the preclinical status may get ahead of itself and human trials do not replicate the desired results. But from the small clinical trials in seizures, pain, nausea, anxiety, and loss of appetite, the results are promising while more research is needed for anti-tumor effects in humans.
As with any medication, there will be clear-cut side effects just as with any other medication which is why more studies are needed to determine the least amount with the least amount of side effects. In some studies, amounts upwards of 50mg/kg (2) is used the high amounts likely responsible for causing side effects, which is far higher than that cautioned by medical marijuana dispensaries. It will take patients time to wrap their heads around taking guidance from a fresh-faced 20-year-old millennial at the spa-like dispensary which is currently the norm at most dispensaries, who likely knows much more than even most medical professionals. It seems it will take even longer in Congress to understand the potential benefit of cannabinoids from a medical standpoint especially with the present opioid epidemic. Countries in Europe have far surpassed the United States when it comes to cutting-edge treatments. Perhaps, it will take even longer for the medical community to see the medical potential with their exposure to the sinister side of tetrahydrocannabinol seen in patients in the ER for non-medical reasons, which may be one of the most challenging stumbling blocks.
Virginia Thornley, M.D., Neurologist, Epileptologist
March 10, 2018
Cannabinoids, which are cannabis plant-based non-synthetic medications including cannabidiol (CBD) and tetrahydrocannabinol (THC), are being used more frequently in palliative care to reduce the pain associated with end-stage cancer. In addition, it is well-established that it helps with lack of appetite found in cancer patients and reduces nausea and vomiting associated with many of the chemotherapeutic drug regimens (2), although current studies are needed given the newer chemotherapeutic agents available. Although there were more reported side effects using cannabinoids including euphoria, dizziness, dysphoria, and somnolence it is not clear if low dosages were used or what the ratio of cannabidiol to THC was used. It is well known that using higher doses of THC products will control the pain more adequately but at high doses may cause the side effect. Cannabidiol alone has no intoxication or euphoria and a low dose of cannabidiol combined with THC will ameliorate some of the side effects of THC. Questions regarding its anti-tumor properties often arise which physicians managing patients with cancer are not prepared to answer. Since most of the studies are done in animal models and are often difficult to translate into the human model, research is needed with randomized clinical trials in the patient population. Currently, most anti-tumor literature is found in cell culture lines and extrapolated. The future is promising but large human studies are needed.
In renal cancer
Cannabinoids work through 2 receptors CB1 found in highest numbers in the brain and CB2 which is predominant in the immune system. In renal cancer, the CB1 receptor is found to be lower in number which may suggest that a reduced number of cannabinoid receptors leads to less control over the proliferation of tumor cells. There is a high concentration in the proximal convoluted tubule which suggests that a down-regulation may be associated with less inhibition of tumor cell proliferation (1). In another study, CB1 receptors were similar in chromophobe tissue lines were similar to renal cells with no tumor. This may serve as a diagnostic tool for differentiating it from clear cell tumors. It is often difficult to differentiate between the two. Chromophobe tumors have the same number of CB1 receptors while clear cell carcinomas have less CB1 receptors. This is important from the histological and diagnostic standpoint (1).
In prostatic cancer
In prostate cancer, some mechanisms suggested through studies include working through phosphatase induction. It was found that CB1 and CB2 are expressed during later stages of prostatic cancer. Treatment of prostate cancer culture cells with cannabinoids was found to reduce the multiplication of tumor cells, suggesting a role through apoptotic mechanisms. The effect was dependent on dosage. In another study, cannabinoids were found to increase cytokine IL-6 in prostate cancer that is androgen resistant. This suggests that CB2 agonists may play an important role in reducing epithelial cell proliferation and may lead to a means to treat prostatic cancer (1). More studies are needed to elucidate mechanisms leading to treatment of prostatic cancer.
In bladder cancer
There is much evidence that inflammation found in cancer may lead to the metastatic stage. Cancer can lead to a pro-inflammatory state inducing cytokine and growth factor release leading to the environment conducive to metastasis and invasion of cancer cells into other tissues. In one study of the CB1 and CB2 receptors, it was found that activation of CB1 receptors played an important role in regulating tumor cell proliferation while CB2 was important in influencing an inflammatory state (1). Further studies are needed to further elucidate the mechanisms of cannabinoids on bladder cancer.