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Reference

Thiele, et al,. “Cannabidiol in patients with seizures from Lennox Gastaut Syndrome (GWPCARE4): a randomized, double-blind placebo-controlled phase 3 trial,” Lancet, 2018, Jan., 390 (10125):1085-1096.

Post-Traumatic Stress Disorder

Post-traumatic stress disorder and traumatic brain injury among military veterans and use of non-intoxicating medical marijuana as a treatment

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

March 28, 2018

Introduction

Post-traumatic stress disorder occurs due to a single or a sequence of traumatic events which causes a great deal of anxiety when exposed to situations similar to the event. Flashbacks and nightmares may occur. In military veterans returning from the Iraqi or war in Afghanistan and even to this day in Vietnam War veterans, emotional disruption is noticeable. It is difficult to know if this is related to blast injury or is a symptom of post-traumatic stress disorder.

PTSD correlated with mild traumatic brain injury

In a retrospective study reviewing medical records of 27,169 military personnel of the U.S. Army Special Operations Command (USASOC), 2831 met criteria of mild traumatic brain injury using the Immediate post-concussion assessment cognitive test, PTSD checklist, and the post-concussion symptom scale. Of these, 28% exhibited symptoms of post-traumatic stress disorder. Military veterans of blunt, blast or a combination injury had a higher percent of meeting criteria for post-traumatic stress disorder than those without mild traumatic brain injury. Those with blast/combination injury had a higher percent of post-traumatic stress disorder and performed worse with visual memory and time for reacting compared the cohort without any blunt or mild traumatic brain injury. Repetitive exposure to blast-type injuries may have a lingering effect (2). This study found a high degree of PTSD symptoms in those with blast, blunt and combination injury compared to the cohort without it.

In a study, disrupted emotional responses correlate with PTSD rather than blast-related traumatic brain injury

Another study tried to dissect whether the emotional responses of war veterans are due to PTSD or due to the mild brain injury itself. In one study of 123 military veterans from the war in Iraq and Afghanistan, affective evaluations and psychological assessments were made in response to pleasant, neutral, unpleasant and war-related images. Those with emotional disruption due to PTSD rated pleasant images as unpleasant and had increased physiological responses towards combat-related images. Symptoms of post-traumatic stress disorder included increased skin conductance responses, greater corrugator muscle electromyography responses, and reduced heart decelerations. There were no effects noted in veterans with mild traumatic brain injury. This points towards the emotional disruption seen in military veterans as related with post-traumatic stress disorder rather than due to the mild traumatic brain injury itself. This study may help guide treatment as military veterans transition to civilian life (1).

Medical marijuana and mechanism of action, a non-intoxicating solution when cannabidiol is used alone or in conjunction with low dose tetrahydrocannabinol

Cannabidiol is a non-intoxicating endocannabinoid that works within the endocannabinoid system found naturally in our systems. It has only a weak affinity to the CB1 receptor which is found abundantly within the neurological system. CB1 receptors are found to be increased in response to cerebral cell damage and seem to work as a repair mechanism for neural systems that are not functioning. Tetrahydrocannabinol at low concentrations has medical properties without the intoxication of high dose THC. THC should be used in combination with CBD to offset the possible side effects such as hyperactivity.

There are increasing studies showing the value of medical marijuana, especially in the central nervous system especially given the large abundance of the CB1 receptor within the nervous system. The receptors are found to be upregulated in the face of disease suggesting a cell repair role or a response to the abnormalities within the brain, For example, in patient with seizures, the CB1 receptor is found to be increased in the temporal lobe within the dentate gyrus compared to other cells almost as a response to the aberrant system within the cortex. The receptors are found to be increased in patients with Parkinson’s disease.

Medical Marijuana as a solution for symptoms of cognitive impairment in war veterans

In one study, 24 patients were enrolled in a study for executive function and were registered medical marijuana users. After 3 months, 11 patients returned and using the Stroop Color Word Test, were found to have a higher level of executive function and increased speed completing tasks without being inaccurate. Patients reported less insomnia, less depression, better attention, less impulsivity and a better quality of life. There was less use of pharmacologic use and less use of opioid agents by 42% in conjunction with medical marijuana. Larger clinical randomized controlled clinical studies are needed.

Medical marijuana seems to be an excellent agent in those affected by traumatic brain injury.

Medical Marijuana as a solution for and PTSD symptom in war veterans

Cannabidiol works at the level of the 5HT1 receptor causing patients to feel less anxious and may be used in post-traumatic stress disorder. In addition, it has been found to have a role in modulating memory and instead of the learned fear response and may help with PTSD by modulating the conditioned response to a stimulus that normally begets anxiety and fearfulness. In other words, instead of the heart rate increasing or having flashbacks when a war scene is on TV, medical marijuana can exert its effect by modulating behavior by changing the learned response by not responding the same way and being calm in face of a previously anxiety-inciting war scene(4).

In conclusion

In summary, PTSD and traumatic brain injury are real problems faced by war veterans returning with blast injury, blunt-injury or combination type combat-related injuries. Medical marijuana may be an excellent non-intoxicating solution when cannabidiol is taken or combined with low dose tetrahydrocannabinol which can help with depression, anxiety and help modulate responses to post-traumatic stress disorder. Medical marijuana can help with executive function and attention and may be beneficial in treating war veterans suffering from mild traumatic brain injury.

References

Marquardt, et al, “Symptoms of Post-traumatic stress rather than mild traumatic brain injury best account for altered emotional responses in military veterans,” J. Trauma Stress, 2018, Feb., 31 (1):114-124.
Kontos, et al, “Residual effects of combat-related mild traumatic brain injury, “J. Neurotrauma, 2013, Apr., 15, 30 (8):680-6.
Gruber, et al, “Splendor in the Grass? A pilot study assessing the impact of medical marijuana on executive function,” Front. Pharmacology, 2016,. Oct., 13 (7):355.
Uhernik, et al, “Learning and memory are modulated by cannabidiol when administered during trace fear-conditioning,” Neurobiology of Learned Memory, 2018, Feb., 9, 149:58-76. doi: 10.1016/j.nlm.2018.02.009 (Epub ahead of print)

chronic pain

Medical Marijuana: a non-intoxicating pain-relieving solution to the opioid epidemic?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 24, 2018

Introduction

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 conclusion

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.

Anxiety, Depression, Post-Traumatic Stress Disorder, Uncategorized

Cannabidiol and tetrahydrocannabinol: effectiveness in post-traumatic stress disorder, anxiety and depression

Virginia Thornley, M.D., Neurologist, Epileptologist

March 20, 2018

Post-traumatic stress disorder is the silent disorder that could be affecting the co-worker who sits one cubicle over from you. When one hears of post-traumatic stress disorder, one thinks of traumatizing incidents such as war, abuse or some other devastating event but can occur even in situations such as car accidents or a spouse of many decades suddenly leaving. It is the quiet disorder that if you do not expound on it, nobody really knows about it. Because of the stigma surrounding psychological disorders, often times, help is not sought in a timely manner.

It is often characterized by nightmares waking someone up in the middle of the night or sudden flashbacks when placed in a situation similar to the traumatic event. Management includes working with a psychiatrist using conventional medications and a psychologist using behavioral therapy. It is not uncommon for a patient to have to go through many different anti-depressants or anxiolytics before one finds the correct drug and titration. But sometimes even the best medications fail to treat someone with Post-traumatic stress disorder adequately. Psychotherapy may be helpful in some patients depending on the patient. In others, there is less benefit and some dislike the thought of reliving the experience in order to learn coping mechanisms.

Alternatives include non-pharmacologic measures including relaxation techniques such as doing yoga, Tai Chi or meditation. Exercise can often boost the mood and doing enjoyable activities may help alleviate symptoms without the addition of pharmacologic agents. Doing something one enjoys or taking joy in the simple activities in life such as writing poetry, art therapy, taking up a sport may help alleviate some of the stress. Great tips can be found on Psychiatrist, Dr. Welby’s site found here: https://drmelissawelby.com/exercise-depression-get-started-want-stay-bed/

More and more patients are turning towards alternative measures, finding that conventional medications are not always optimal. Cannabidiol works through the endocannabinoid pathway and modulates its effect through the CB1 receptor which is predominantly found in the nervous system. The CB2 receptor is found mostly in the immune system. In some studies, it was found that cannabidiol may help reduce fearful memory if taken in the conditioning phase so that rather than reacting to the stimulus with fear, the stimulus is then associated with a different reaction and may help mitigate the symptoms of post-traumatic stress disorder through this mechanism (1). In another study, it was found to influence synaptic dendrites and may contribute towards learned memory in the hippocampus (2).

Cannabidiol interacts with the 5HT-A receptor which is an important receptor in mitigating the symptoms of anxiety. Serotonin works through the 5HT1-A receptors. Some anxiolytics and anti-depressants work through an increase in serotonin which boosts the mood. Cannabidiol itself is known to have a calming effect with none of the euphoria found in THC alone. Cannabidiol is non-intoxicating and when combined with low dose tetrahydrocannabinol has great medical effects.

In summary, when medications and therapy are found to be ineffective for post-traumatic stress disorder, anxiety or depression, cannabidiol which is non-intoxicating may be an effective therapeutic option alone or in conjunction with low dose THC and should be considered.

References

Uhernik, et al, “Learning and memory are modulated by cannabidiol when administered during trace fear-conditioning,” Neurobiology of Learned Memory, 2018, Feb., 9, 149:58-76. doi: 10.1016/j.nlm.2018.02.009 (Epub ahead of print)
Lee, et al, “Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorder,” British Journal of Pharmacology, 2017, Oct., 174 (19): 3242-3256. doi: 10.1111/bph.13724. (Epub. 2017 Mar. 9.)

Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D. Neurologist, Epileptologist

Introduction

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 conclusion

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.

multiple sclerosis

Sativex (tetrahydrocannabinol and cannabidiol) and the European experience in medically refractory spasticity in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist

March 12, 2018

Introduction

Sativex has been available in Europe since 2010. It is a combination of tetrahydrocannabinol and cannabidiol at a ratio of 1:1 and has been found to be effective in spasticity resistant to medications in patients with multiple sclerosis. Spasticity is the increased tone seen in the muscles due to abnormalities in the central nervous system such as the white matter lesions seen in multiple sclerosis.

Sativex and medically refractory spasticity in multiple sclerosis

Sativex is a THC:CBD (tetrahydrocannabinol:cannabidiol) preparation taken oromucosally which was approved in European countries for the treatment of medically refractory spasticity in patients with multiple sclerosis. Sativex contains a 1:1 ratio of THC to CBD, where THC interacts with CBD receptors to reduce spasticity while CBD ameliorates the side effects often seen with THC. In one large clinical trial of 1615 patients, 42% showed improvement of spasticity in the first 4 weeks, defined as > or = to 20% reduction in spasticity. The responders were double-blinded and grouped under placebo or THC:CBD, a larger proportion of patients had significant response compared to placebo, > or = to 30% reduction of NRS score for spasticity. 47% had adverse effects including fatigue and dizziness. Reported side effects included psychiatric disturbances, 55 had cognitive (attention problems, cognitive worsening and memory problems) and psychiatric issues (confusion, panic attacks, hallucinations, depression and suicidal ideations). Fatigue, drowsiness, dizziness, gastrointestinal symptoms, mouth discomfort and allergic reactions were other reported side effects. There was no evidence of abuse or addiction in the patients. There were significant side effects deemed unrelated to Sativex including, myocardial infarct, hypertensive crisis (2).

In the original MOVE 2 trial in Italy, in the 322 patients studied, the NRS numerical rating scale decreased by -19.1% from baseline time to 3 months of treatment with Sativex. At visit 3 at 3 months, 24.6% were considered relevant responders to the medication with 30% or more reduction in spasticity. Side effects of >1% included somnolence, dizziness, and fatigue. 41 patients reported side effects 3 were serious side effects of which one was not related (3).

IMG_5833_preview

Sativex and studies in Germany, United Kingdom, Switzerland and Spain

Sativex was first approved in Spain and the United Kingdom in 2010 for use in spasticity related to multiple sclerosis. Data were collected to study continued efficacy and safety profiles. 941 patients (761 from the UK, 178 from Germany and 2 from Switzerland) were studied. Data was collected up until January of 2015. A patient registry was set up as per guidelines before new medications are approved. Patients from the UK were 22% of the patients registered in the UK using that medication since 2010. Continuation rates were 1 year for 68% of patients. Among those who stopped it, 30% cited lack of effectiveness and 25% described side effects. Some significant side effects include suicidality in 2% and depression in 6%. There was no evidence of abuse, addiction or misuse. The fatigue was within the known safety margins of the drug. The patients used on average 5.9 +/- 4.9 sprays per day

In Spain, 204 patients were evaluated. After 6 months, 143 (70.1%) had benefited from using it for spasticity. After 12 months 64.7% derived beneficial effects. The average dose was 6.6 sprays a day. 41 patients had side effects consisting of psychiatric events, falls, reduced the ability to drive and others. Both study groups in the UK, Germany, Switzerland and in Spain both derived benefits justifying continued used of Sativex. Adverse effects were low, and the mean use of sprays was between 5.9-6.6 which was lower than the clinical trial using 8 sprays (4).

Sativex and timeline when it is found to be ineffective

In one large study in Italy involving 30 multiple sclerosis centers, the discontinuation profile was studied. Patient data from 30 MS centers were collected from a period of January 2014 to January 2015. 39.5% of patients disconnected treatment with Sativex. Spasticity was studied using the EDSS or expanded disability status scale and the patient NRS numerical rating scale 0-10 for spasticity. Information was collected at baseline (T0), 4 weeks (T1), 3 months (T2) and 6 months (T3).

Spasticity was noted in 1615 patients. 1597 (39.5%) discontinued treatment. Of those, 24.8% did not reach 20% effectiveness using the NRS scale. Reasons of discontinuing include lack of effectiveness 23%, side effects 16.3% and lack of compliance 0.8%, lost to follow-up 0.4%, patient choice 0.3% and unknown reasons 2%. Analysis showed that an increase in the NRS scale by 1 point at baseline time corresponded to a lower rate of discontinuation. While an increase in the NRS scale at timeline 2 or at 4 weeks corresponded with worsening spasticity and a higher non-responder rate. They concluded that Sativex is a good option for spasticity and by 4-6 weeks, patients can be reliably identified as responders or non-responders to avoid the cost burden on the healthcare system (1).

german tripand old pics 410_preview

Reference

Messina, et al, “Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study), Public Library of Science PLoS One, 2017, 12(8) e0180651
Patti, et al, “Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, 2016, Sep., 87(9):944-951.
Trojano, et al, “Effectiveness and tolerability of THC/CBD oromucosal spray for multiple sclerosis spasticity in Italy: first data from a large observational study,” European Neurology, 2015, 74:178-185,https://doi.org/10.1159/000441819
Fernandez, et al, “THC:CBD in daily practice: available data from UK, Germany and Spain,”European Neurology, 2016, 75 (supp 1);1-3, https://doi.org/10.1159/000444234

Epilepsy, Glaucoma, pain, Peripheral neuropathy, Tumor

Medical Marijuana: why the huge disconnect between physicians, laws, policies, and patients?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 11, 2018

Introduction

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.

In conclusion

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.

References:

Ghandhi, et al, “Systemic review of the potential role of cannabinoids as anti-proliferative agents for urological cancer,” Can. Urol. Assoc. J., 2017, May,-April., 11(3-4):E138-E142.
Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88.
Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.

Epilepsy

Cannabidiol: mechanisms and efficacy in medically refractory epilepsy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 9, 2018

Introduction

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

Mechanisms of Cannabidiol and THC

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

Cannabidiol clinical trials

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

References

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

Peripheral neuropathy

Peripheral neuropathy: chronic pain amelioration with cannabidiol and tetrahydrocannabidiol

Virginia Thornley, Neurologist, Epileptologist

March 8, 2018

Introduction

Chronic pain from neurological conditions such as neuropathic pain can become refractory to conventional medications. Interest is directed towards novel ways of treatment such as cannabidiol and THC which are known in animal models to be anti-inflammatory, analgesic and neuroprotective. Cannabinoids are being used more commonly in patients who have failed medical treatments and remain a viable option in the treatment of pain. Many animal models point towards mechanistic evidence that cannabidiol and THC reduce severity and frequency of pain syndromes. Cannabidiol is non-intoxicating and is an alternative form of management. With THC, the level of pain relief is higher but with that comes a higher risk of side effects at greater doses.

Cannabidiol and neuropathic pain in joints

Osteoarthritis involves inflammation, pain, and neuropathic pain. Cannabidiol was studied in rat models and its effect on pain from the joints and nerves. In end-stage osteoarthritis, cannabidiol reduced joint afferent pain. Transient joint inflammation was reduced using cannabidiol. CBD application used prophylactically demonstrated lack of development of pain and inflammation during later stages.

One study suggests that chronic neuropathic pain might be suppressed by cannabidiol through alpha 3 glycine receptors. In mice lacking these receptors, there is no cannabidiol analgesic effect. Cannabinoids are found to support glycine activity in the dorsal cell neurons in rats. This suggests that glycinergic cannabinoids may provide a potential therapeutic option in treating neuropathic pain. There is lack of psychoactive side effects or development of tolerance (1).

Cannabidiol and neuropathic pain studies

In one review of 15 randomized controlled trials against placebo with a total of 1619 patients, 13 studies consisting of 1565 patients reported a reduction of pain compared to placebo which was statistically significant. There was a frequency reduction in pain of 30%. 10 studies used nasal tetrahydrocannabinol /cannabidiol and 3 used synthetic cannabidiol while 2 used medical cannabis. They concluded that cannabidiols were marginally superior and had greater side effects than placebo. It is a treatment option for patients who have failed several lines of treatment. Some flaws that can be seen in this study is that with this study, some centers used synthetic forms of cannabinoids and others used a combination of THC and cannabidiol. Synthetic medical marijuana has a different quality compared to a product that is purely organic and made from natural materials. High doses of THC is known to cause side effects while with lower doses of THC pain relief may be obtained with fewer side effects. It is not clear how pure the products are which were being administered.

In one large study of 303 patients with peripheral neuropathy, 128 used CBD/THC spray and 118 randomized to placebo. End-point was a 30% responder rate using the PNP numerical scale 0-10. There was a substantially higher number of responders for CBD:THC but not statistically significant. Quality of life and sleep improved in those with CBD/THC nasal spray. They concluded that use of CBD/THC helped improve pain from peripheral neuropathy and there were no substantial adverse effects from the patients studied (3).

Xiong, et al, “Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha 3 glycine receptors,” Journal of Experimental Medicine, 2012, Jun., 209(6):1121-1134.
Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88
Serpell, et al, “A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment,” European Journal of Pain, 2014, Aug., 18(7):999-1012.

Amyotrophic lateral sclerosis

Non-pharmacologic aspects of ALS: correlation of higher BMI with greater survival, beneficial use of cannabidiol, respiratory evaluation, exercise and anesthetic considerations

Virginia Thornley, M.D., Neurologist, Epileptologist

March 4, 2018

ALS is a progressive neurodegenerative illness which affects the lower motor neurons causing progressive weakness and eventually respiratory failure. There are currently only 2 prescription agents available for slowing the progression of the disease. Management is largely symptomatic treatment of debilitating symptoms. Much consideration is being directed towards alternative treatments such as dietary considerations and use of cannabidiol.

ALS and supplements and BMI

Based on one large review of studies, there was not enough evidence to support recommendations of Vitamin A, and C or Coenzyme Q10. For Vitamin B complex, Homocysteine, Vitamin D, there is limited data which is not enough to support or refute recommendation, more clinical trials are needed. Vitamin E may be beneficial in preclinical patients with a familial tendency. Omega-3 was found to accelerate disease progression with increased vacuolization of anterior horn cells and are deleterious in presymptomatic patients. L-Carnitine may increase survival time with a slower ALSFRS or ALS functional revised score and greater FVC volumes but more trials are needed (1). Body mass index of less than 18.5kg/m is found with less survival time, while those with a higher BMI have greater survival time. One small study suggested a high calorie, hypercaloric enteral diet was tolerable in patients but unclear if associated with better outcome in terms of survival time.

Cannabidiol as a novel therapeutic agent

Cannabidiol is known in animal models to be anti-inflammatory and anti-oxidant. In the G93A SOD-1 mouse model, it was found to slow progression of the disease and increase survival time. In a study of 13 patients, it reduced drooling, loss of appetite, pain, and spasticity.

In one study, cannabidiol was used in human gingiva-derived mesenchymal stromal cells. The transcriptomic sequence in the next generation shows a change in gene expression in ALS related genes. There was a change in the genes connected to ALS regarding oxidative stress, mitochondrial dysfunction and excitotoxicity in the human gingiva-derived mesenchymal stromal cells when treated with cannabidiol. This suggests that cannabidiol may serve as a modulatory role in the early pathogenesis of ALS (2).

Other aspects of ALS

Exercise

Studies regarding exercise showed flaws in methodology or were in small numbers. Therefore, based on available studies it is unclear if exercise benefits a patient’s long-term outcome.

Sialorrhea

Sialorrhea should be addressed. Aside from conventional medications, other options include botulinum toxin and small doses of radiation therapy delivered to the salivary glands.

Anesthesia

Anesthetic agents such as neuromuscular blockers are contraindicated in patients with ALS due to the risk of increased potassium release. In one study of 51 patients with ALS, general anesthesia was safely administered.

Pulmonary function

Pulmonary function tests are monitored every few months depending on the rapidity of the progression of the disease. Non-invasive positive pressure ventilation is used in patients with ALS with an oral or nasal mask. As force vital capacity (FVC) declines, it may be administered through a bi-level positive airway ventilation machine continuously at night(1).