Cannabidiol: a large study in the U.S., Netherlands, and Poland shows its efficacy in patients with the epileptic disorder Lennox-Gastaut Syndrome
Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD
March 31, 2018
Introduction
Lennox-Gastaut Syndrome is an epileptic syndrome starting in childhood characterized by a wide spectrum of seizures and slow spike and wave on EEG. The seizures are characterized by the classic mnemonic “a fall, a jerk and a stare” or atonic seizures, myoclonus and complex partial seizures, although there are many other different types. Slow spike and wave generalized epileptiform discharges of 2.5 Hertz or less on electroencephalogram clinch the diagnosis. Patients are often delayed in development. Controlling seizures, because of the sheer complexity, of the different types is often a medical challenge.
Methods of the study
A new study using cannabidiol, which is the non-psychoactive medical component of the cannabis sativa plant, was carried out with the results recently demonstrating value. It covered 24 sites from the U.S., the Netherlands and Poland and studied seizures in patients medically refractory to medications using cannabidiol as an adjunctive add-on agent. 171 patients were enrolled from April 28, 2015, to October 15, 2015, and were randomly assigned to either the placebo control or the group with cannabidiol. 86 received cannabidiol and 85 were in the placebo group. 14 discontinued treatment in the cannabidiol group and 1 in the placebo group. All patients had at least one dose of treatment. Eligible patients ranged from 2-55 years old. Cannabidiol was given at a dose of 20mg/kg.
Seizure reduction
The results were startling, there was a reduction of seizures by 43.9% in the cannabidiol group and 21% in the control group. 86% patients had side effects in the cannabidiol group and 69% in the control group on placebo. These included somnolence, pyrexia, diarrhea, reduced appetite, and vomiting. 12 stopped in the cannabidiol group due to adverse reactions considered mild to moderate while 1 withdrew from the placebo group. 1 died due to unrelated causes from the cannabidiol group.
Conclusion
Reviewing this study, perhaps one of my critiques of this study is that the dosage was 20mg/kg in a 14-week study which means that within 14 weeks a patient of 50 kg. would have been ramped up to about 1000mg. In real life practice, medications are titrated more gradually over a period of months before maximum efficacy may be seen and in such a gradual way in order to avoid side effects. Although a large percentage of patients had side effects which were mild to moderate, it is quite possible they may have needed a smaller dose and the dosages were increased more than it was necessary to achieve the beneficial effects seen in the study within a short period of time. Nevertheless, the bottom line is that cannabidiol, a product of the Cannabis sativa plant, shows a reduction in seizures in a patient with Lennox-Gastaut syndrome.
This study concluded that there is some efficacy of cannabidiol in Lennox-Gastaut syndrome, one of the most difficult epileptic syndromes to treat, and was found with only very mild to moderate side effects. An open-label study as an extension to this study is currently ongoing.
Neurologybuzz.com
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.
Ketogenic diet, modified Atkins diet and what is in them: used in seizure control, can these be a weight loss solution to morbid obesity, a risk factor for cerebrovascular and cardiovascular disease?
Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD
March 29, 2018
Introduction
Ketogenic diet has been used for seizure control when physicians started to notice a reduction of seizures in patients with a high ketone laden diet. This fell out of favor in the 1920’s with the onset of newer agents. As a side note, weight loss has been noted in those on a ketogenic diet.
Previously, guidelines have recommended a reduction in saturated fat which was thought to be the cause of the growing morbid obesity epidemic. Currently, it has been found that carbohydrates which are rich and refined may contribute towards the obesity epidemic. Sugar-laden sodas, the white bread which has refined flour, pizza batter made out of refined flour, all these food which are popular in theIt is no Western culture contribute to the morbid obesity as it is looming today.
How current culture sets the perfect stage for morbid obesity
The current western diet is about 50% carbohydrates. In addition, physical activity is at an all-time low compared to other eras. The current culture is designed as a sedentary and carbohydrate-rich eating culture. Everything nowadays is rapid pace. There are drive-through banks, drive-through pharmacies. Rather than having to physically go to a shop or order things in person, many things can be done online or by phone reducing the daily need to exert physical activity. There is less time spent on physical activity compared to 100 years ago. If you go to neighborhoods, sidewalks no longer exist. Unless one lives in an urban environment where you are forced to walk to the bus station or live in cities amenable to walking or biking, the car is the mode of transport. Food is rich in carbohydrate, such hamburger buns, pizza dough, white bread or rolls. It is little wonder that morbid obesity abounds. Food rich in sugar is abundant in grocery store aisles including donuts, cookies, baking packets. The colorful rich in anti-oxidant fresh fruits and vegetables are usually on the sides of the grocery shops, the food that is actually good for you and you need to take time out of your schedule to cook.
Living a healthy diet is not just staying active but also eating the proper diet. Food that is closest to their original source are richest in nutrients. In short, the colorful vegetables you have to cook without any of the processing that takes place are the food richest in nutrients and have high anti-oxidant properties. Anti-oxidation is important in helping to combat a wide variety of diseases. Colorful fruits and vegetables are rich in fiber and more difficult to digest, hence, uses up more calories. Those which are high in refined carbohydrates are easily digested and contributes more towards obesity.
Components of the ketogenic diet and ketogenic diet variants
Ketogenic diet variants include modified Atkins diet, low glycemic index treatment, and medium chain diet. The ketogenic diet consists of 4:1 ratio of fat to carbohydrates shifting metabolism to the use of ketone bodies as a source of energy. A lower ratio is sometimes employed called the modified ketogenic diet with a 3:1 or 2:1 ratio of fat to carbohydrates. In the modified ketogenic diet, the palatability is improved and avoids the gastrointestinal symptoms associated with the ketogenic diet such as nausea. With the modified Atkins diet, carbohydrates are restricted to 10-20 grams a day, or a 1-2:1 ratio of protein to fat plus carbohydrates. In the low glycemic index treatment, carbohydrates are limited to 40-60 grams while 50-60% of the diet is fat and 20-30% is from protein. The medium-chain triglyceride diet employs oils as a supplement such as coconut oil. The palatability of these diets improve patient compliance and lessen the side effects of the ketogenic diet. Some patients also used the diets to incidentally lose weight in addition to treating seizures.
Ketogenic diet and evidence it works in losing weight
The ketogenic diet has a carbohydrate component of about 20-50 grams a day. It is not so much the restriction of the carbohydrates but the quality of carbohydrates that are ingested that causes people to shed pounds. High fiber, wheat, and whole grain carbohydrates portend a healthier diet as opposed to just restricting carbohydrates in general. In some clinical studies, it was found that weight loss was higher in those with a low carbohydrate diet compared to a low-fat diet (1).
Will the high fat cause me to have heart disease?
In one study where ketogenic diet was used in glucose transporter deficiency, a pediatric epileptic syndrome with encephalopathy, 10 patients were followed for 10 years. After 10 years on ketogenic therapies, there was no evidence of increased cardiovascular risk. While it is a small study, it shows evidence that eating a low carbohydrate diet did not appear to contribute towards heart disease. Larger clinical trials are needed (3).
How obesity relates to other diseases
It is not uncommon to see patients who come into the ER or the doctor’s office with a history of hypertension, diabetes mellitus type II, hypercholesterolemia and obesity all related to one common denominator-obesity. Take away the obesity, the bad cholesterol or the LDL values go down, glucose goes down and hypertension resolves. When these risk factors are reduced early enough in your life, the odds of cerebrovascular disease or strokes and cardiovascular diseases or heart attacks vastly diminish. If, however, obesity is long-standing, while it is definitely good to reduce risk factors, once atherosclerosis is present in the blood vessels, there is no magic pill to reverse that.
Early identification and reduction of obesity as a contributor towards many health problems is key. Ketogenic diet may play a role in weight reduction. A small case series did not show any risk of heart disease while on the ketogenic diet long-term, over a span of 10 years. Larger clinical trials are needed to support this.
Reference
- Giugliano, et al, “More sugar? No thank you! The elusive nature of low carbohydrate diets,” Endocrine, 2018, Mar, 19. doi: 10.1007/s12020-018-1580-X (Epub ahead of print)
- McDonald, et al, “Ketogenic diets for adults with highly refractory epilepsy,” Epilepsy Currents, 2017, Nov.-Dec., 17 (6):346-350.
- Heussinger, et al, “10 patients, 10 years-Long-term follow-up of cardiovascular risk factors in Glut1 deficiency treared with ketogenic diet therapies: a prospective , multicenter case series,” Clin. Nut., 2017, Nov, pil:S0261-5614 (17)31399-7.
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.
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)
Seizure alert dogs: can they really sense seizures of their owners?
Virginia Thornley, M.D., Neurologist, Epileptologist
March 28, 2018
Introduction
Seizures are a result of recurrent electrical impulses in the brain causing repetitive symptoms pertaining to that area. At times, patients will not know when they occur.
Scientific studies
Seizure alert dogs are used to detect seizures that are undetectable to humans which may be either through olfactory senses or a change in the behavior. In one study, patients utilizing the seizure alert dog were studied. Seizure frequency was monitored for 48 weeks including a baseline of 12 weeks after entry into the study. With this mode, there has been a seizure reduction of about 43% compared to baseline. 9/10 patients had a 34% reduction in seizure frequency (1).
One study suggested that dogs have the innate sense of sensing their owners’ seizures. In 63 patients, 29 had pet dogs, 9 stated their dogs could sense their seizures (3).
In some studies of skeptical value, there is no proven benefit, although the presence of pseudoseizure may be a factor, meaning neurological symptoms that appear as seizures but are psychogenic in etiology may throw the seizure alert dogs off. Although some studies may indicate lack of benefit, mode of training may play an influence in the detection. The seizure alert dog likely takes cues from the heart rate or olfactory cues to detect seizures (2).
Downsides to seizure alert dog services
Recipients of service dog must meet certain criteria. This service is usually not covered by medical insurance and patients may avail of this service through assistance programs for a minimal fee.
The service dogs themselves may suffer from stress related to the work required for service. In addition, most dogs train between 6 months and 2 years after which service may be of value for about 7 years. The patient must also forge a bond with their service animal. Becuase it is often not covered by insurance and it may be cost prohibitive, some patients have started training their own dogs for seizure detection. The different levels of training may not be standardized or adequate.
References
- Strong, et al, “Effect of trained seizure alert dogs on the frequency of tonic-clonic seizures,” Seizure, 2002, Sep., 11(6):402-405.
- Brown, et al, “Can seizure-alert dogs predict seizures?” Epilepsy Res., 2011, Dec., 97(3):236-242.
- Dalziel, et al, “Seizure-alert dogs: a review and preliminary study,” Seizure, 2003, Mar., 12 (2):115-120.
- Strong, et al, “Seizure alert dog-fact or fiction?”Seizures, 1999, Feb., 8 (1):62-65.
Epilepsy surgery in temporal lobe epilepsy due to mesial temporal sclerosis: the timeline in investigative work-up from the neurologist’s office to the O.R.
Virginia Thornley, M.D. Neurologist, Epileptologist
March 27, 2018
Introduction
Temporal lobe epilepsy is one of the most common types of seizures. The most common cause and one of the most successfully treated causes of temporal lobe epilepsy treated through surgery is mesial temporal sclerosis. This article focuses on mesial temporal sclerosis and does not include discussions of other types of temporal lobe epilepsy due to other causes such as tumors, cystic lesions or head injury or non-lesional temporal lobe epilepsy. In order to identify a patient, the symptoms are generally stereotypical which suggest localizing towards one focus. An early age of identification may portend a better outcome since frequent temporal lobe seizures may cause the development of circuitry to the opposite side causing another focus to develop on the opposite temporal lobe. In addition, it is important to control temporal lobe epilepsy because of the location of the seizures are in the hippocampus which is important in memory. Many patients complain of poor memory which will continue to progress should seizures remain poorly controlled. Epilepsy surgery is the definitive treatment for temporal lobe epilepsy in mesial temporal sclerosis.
Identification
To identify an appropriate candidate for surgery, the patient should have stereotypical seizures which localize towards one focus. While the focus may cause contralateral clinical symptoms, automatisms of the limb are generally ipsilateral to the focus. Once a patient has been identified, further diagnostics tests are needed in order to confirm this focus including a routine electroencephalogram and an ambulatory 48-72 hour EEG which can be performed out-patient. The only downfall with an ambulatory EEG is that it is subject to the artifact, since the electrodes may be displaced causing poor adherence of the electrode to the scalp causing resistance manifested as artifact and a poor recording. However, it is still a good screening test to determine whether there may be a single focus versus multiple regions affected. Temporal lobe epilepsy may be seen with high voltage epileptiform spike and wave. It may be accompanied by focal delta slowing within the temporal lobe, suggesting temporal lobe dysfunction due to recurring seizures. If a patient is deemed an appropriate candidate, a referral may be made to an epilepsy center where more in-depth investigations are performed.
Admission to an epilepsy center
Expect to stay at least 1 week or more in order to allow the capture of typical seizures and to obtain an adequate sampling of ictal periods and pinter-ictal periods during wakefulness and sleep. A team of specialists is involved with the work-up including a clinical epileptologist who manages the medications and clinical aspect, a clinical neurophysiologist who interprets the video EEG monitoring and correlates it with the clinical symptoms, a neuropsychologist who performs the WADA testing and a slew of clinical EEG technicians who ensure that the electrodes are properly attached throughout the hospital stay. In-depth conferences are held to review the studies of the patients and evaluate which patients are suitable epilepsy candidates. Sometimes, multiple admissions are necessary before seizures can be captured.
Hospitalization
During admission, seizures are captured and correlated with the electroencephalographic recordings to determine the focus. More than one focus correlates with a poor outcome, a single focus is necessary. The clinician may provoke seizures by tapering medications safely in the hospital setting. Other techniques include sleep deprivation and encouraging any triggers. The full spectrum of clinical seizures must be captured in order to ensure adequate localization. Bitemporal foci portend a poor outcome.
Neuroimaging
A high-quality MRI of the brain using epilepsy protocol with thin cuts through the temporal lobes of 1.5mm to 2mm is essential. Coronal views are the best way to visualize the hippocampi to evaluate for hippocampal sclerosis which characterizes temporal lobe epilepsy. Usually, the hippocampus affected is much smaller than the contralateral one with hyperintensity on T2. As a result of excessive seizures, burning off of the cells in the hippocampus occurs so that is it is now atrophic. Although an MRI of the brain may have already been obtained pre-work-up, a higher resolution and exceptional quality brain MRI is likely to be repeated. This will serve as the visual point on which the neurosurgeon operates. Seeing a sclerotic hippocampus gives a high correlation with mesial temporal sclerosis.
Ictal SPECT
Spectroscopy is obtained in-house, where hexamethylpropylenamine oxime (HMPAO) injection is done 30 minutes before an ictus. When the patient has a seizure, the HMPAO perfuses to the area of interest showing where the seizure localizes. Images are obtained. This test has an added value of further localizing the focus. The drawbacks, however, include not being able to predict when a seizure is about to occur and missing the ictus. It is not unusual for this test to be repeated for it to be meaningful. In addition, it can only be done during office hours so that nocturnal seizure will be missed due to lack of adequate staff.
Magnetoencephalography
This is a costly examination which may not be available in some epilepsy centers. It uses a 3-dimensional modality for localizing the focus. The MEG dipoles are superimposed on the MRI images.
WADA testing
A neuropsychologist examines the patient’s memory and language by temporarily putting the opposite side of the brain to sleep through injection of amobarbital into the internal carotid artery. Short-term memory and language are examined. The neuropsychologist must determine that there is adequate memory on the contralateral temporal lobe for temporal lobe surgery to be successful. If both temporal lobes are impaired in terms of memory, the patient will suffer from poor memory following the surgery. Other tests are done by the neuropsychologist to check for cognition, any personality disorders and assess for evidence of mood disorders.
Electrocorticography
This is one of the final steps in the investigation where the cranium over the temporal lobe of interest is removed and electrodes are placed directly on top of the cerebrum. Depth electrodes are placed in order to capture epileptiform discharges buried deep inside the hippocampus which cannot be adequately detected by electrodes laying on top of the temporal lobe. The seizures are recorded and a more accurate mapping of the seizure focus is obtained.
Discussions
Once all the appropriate investigations are obtained, if all the data points towards a single focus then the patient is deemed an appropriate candidate. Epilepsy conferences are usually held and reviewed by all the specialists involved in the care. Some patients may proceed directly into surgery after mapping. Others may need to go home and return back for another admission to undergo epilepsy surgery. A patient who is still questionable may need to return for more in-depth recording, this may occur in non-lesional epilepsy where the information is not strong enough to justify surgery. The goal of epilepsy surgery is to resect the dysfunctional epileptogenic zone while preserving the functioning surrounding cortex.
After care
Once the surgery is performed, the patient will need to be on anti-epileptic agents for at least 2 years of seizure freedom. In appropriately investigated patients, a favorable outcome of seizure freedom may reach as high as 60%.
Anxiety: the science behind anxiety and effectiveness of cannabidiol and tetrahydrocannabinol in anxious patients
Virginia Thornley, M.D., Neurologist, Epileptologist
March 27, 2018
Introduction
Anxiety is a state of unease, the sense of restlessness you feel when you are out of sorts. It may be due to the simple circumstances of being late for a charity dinner to feeling scared out of your wits when your car is trembling on the highway because your wheels are not balanced. Everybody has experienced it at some point in their life. Some more chronically and severely than others. In primitive times, one must redirect their attention from the task of scavenging for food in the jungle to suddenly be alert to imminent danger from the bear prowling behind you. In modern times, one must react quickly to that bus coming at you as you try to cross the street on 51st Street and 5th Avenue. You suddenly look up startled redirecting your focus to the imminently life-threatening event. For someone with clinical anxiety, this would be akin to being fearful every time you try to walk and cross the street despite no threats just the usual fast-paced taxicabs waiting for that green light. There is a chronic response of fearfulness that is not befitting to the situation. Threats are perceived more frequently harboring frequent fearful responses.
Current approach to anxiety
The current armamentarium of a physician includes prescribing anti-anxiety agents, referring to a therapist, recommending relaxation techniques such as yoga, Tai Chi or meditation, or any physician’s all-time fallback choice which is to refer to a psychiatrist. Many medications take weeks to take effect and after all that, not all of them are effective requiring several trials of medications to get to one that may even partially work. A therapist is beneficial, however, cons include the patient not having enough time or resources. In some patients it may help in others, similar to medications, it does diddly squat. In addition, some patients must cope with anxiety through natural means due to the prohibitive nature of their occupation. Some highly sensitive occupations disallow any use of anti-anxiety agents which might be potentially sedating in a patient’s history which could cost them their jobs. Medications may be helpful in certain populations but it often takes time to find the right agent and the right dose.
The science and mechanisms behind anxiety
The mechanism of anxiety and its complexities are studied. At the chemical level, it is thought to be due to the lack of serotonin. Many anti-anxiety agents work at the level of the serotonin receptor. But the thought processes underlying anxiety are far more complex than at a single chemical level which likely is the reason why many medications do not work given the complexity of the emotional response.
Neuroimaging studies have elucidated that anxiety may be attributed to the involvement of an amygdala to prefrontal cortex circuit. Instead of the normal fear response one has to certain stimuli, the amygdala is overly responsive to the threat. This leads to an abnormal attentional and interpretive response level that is consistently fearful. For instance, your bakery might be the best in town but if the client is highly anxious, any little mistake on that wedding cake may be perceived as a personal slight giving rise to an extremely anxious response causing them to want their money back. In other words, the level of anxiety is greatly out of proportion to the situation. There is nothing that bakery could have done to ease that person’s anxiety over the cake.
Patients with anxiety are selectively attentive to threat-related situations. Anxious patients perceive neutral events with negative connotations and potentially threat-related. Stimuli with conditioned threat significance may elicit attention and lead to physiologic responses including increased heart rate, sweating, heavier breathing. This may be the reason why in dealing with an anxious person, no matter what has been said that individual has a hyperalert response and has a very low threshold for a fearful response to a threat-perceived situation when the situation is very neutral (1). For example, you could be the most highly skilled neurosurgeon in the world, if your delivery of the prognosis is a 60% chance of recovery, that could be a source of great angst. The clinically anxious person will hear how she or he will have the 40% chance of not recovering.
Cannabidiol
Cannabidiol is the non-intoxicating phytocannabinoid from the Cannabis sativa plant. It has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria as tetrahydrocannabinol. Cannabidiol is found to help with anxiety. It works at the level of the 5HT-1 receptor to exert its anxiolytic properties. A combination of cannabidiol and tetrahydrocannabinol often called Indica is often used for anxiety and insomnia. It is often used by patients with anxiety primarily at night due to its calming and sedating properties.
In one study of 24 patients with anxiety who were about to give a presentation, cannabidiol was given at 600mg. The anxiety, cognitive impairment, and alert arousal response were much lower compared to the control group who had a placebo. The placebo group had much higher anxiety, greater discomfort, and alert responses (2).
Although federally illegal in many states despite medical marijuana laws and dispensaries popping up around the nation, medical marijuana is an alternative agent that should be considered in patients who are medically refractory to medications, psychotherapy, and other techniques. It has a valuable place in the physician’s medicine bag in treating anxiety and illnesses related to anxiety-related disorders.
References
- Bishop, et al, “Neurocognitive mechanisms of anxiety: an integrative account,” Trends in Cognitive Behavior, article in press.
- Bergamaschi, et al, “Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients,” Neuropsychopharmacology, 2011, May, 36 (6): 1219-26.
The deleterious effect of caffeine on epilepsy and anti-epileptic agents
- Chroscinska-Krawzyk, et al, “Caffeine and anticonvulsant potency of anti-epileptic drugs: experimental and clinical data,” Pharmacol. Rep., 2011, 63(1):12-18.
- Cicvaric, et al, “Sustained consumption of cocoa-based dark chocolate enhances seizure-like events in the mouse hippocampus,” Food Funct., 2018, Mar., 1, 9(3):1532-1544.
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.
Do your spidey senses tingle, better listen up
Virginia Thornley, M.D., Neurologist, Epileptologist
March 24, 2018
Have you ever walked down a quiet lonely corridor of a building where almost everyone has gone home for the day and your spidey senses started to tingle? Or perhaps, you were caught up at work in a facility and it is now 8pm with not a soul in sight and you have a long desolate walk to the parking lot to your car. Your spidey senses tingle as you place your first step out the door leaving the brightly fluorescent-lit building to go out in the cold darkness. Your heart races, your eyes widen checking out your surroundings in front, on the sides and behind you. That is your fight or flight response kicking in in high gear. This is a common scenario where your senses tell you instinctively that you are not in the best situation and you need to be hyperalert to survive a situation should something adverse were to occur.
How about a less straightforward situation where you waltz into a bank minding your own business, you just needed quarters to do your laundry because you live in an apartment building with no washer or dryer. As the teller is getting you a roll of coins, someone comes in from your peripheral vision. You think how rude, I was here first why is this guy cutting my line? He has sunglasses, a hat and holds up a note to the teller while telling you to be chill, be chill. Then it dawns on you that you are suddenly in the middle of a bank heist. Do you a) scream and ask for assistance from the security guard standing 2 feet away? b) run for your life because the man beside you has his hand in his pocket and you could turn into smithereens in the next few seconds c) stay frozen as your life passes through your mind thinking hmm, what should I do scream for assistance or be chill like the guy reassuringly told me to be. Your mind instinctively tells you it is prudent to do the latter. This is another situation where you are on edge, your systems are overloaded with information and your mind is racing like a marathon on what was the best case scenario to get yourself out of that situation.
Many times in our life we are faced with situations when we feel potential threat or fear of the unknown and lightning speed logic and actions are required. Our bodies are designed to react quickly to situations. The amygdala has an emotional function in our brain that directs our reactions when the unnerving situation is detected. Signals are sent to the hypothalamus in the brain that connects with the adrenal medulla which lies on top of the kidneys and from where epinephrine and norepinephrine are released The sympathetic nervous system is the system that allows our pupils to dilate, our heart to pump quickly and our palms to sweat. It is part of the autonomic nervous system that controls and regulates the cardiac muscles, muscles, and glands. During fight or flight response to stress, there is an adrenergic rush when epinephrine is released and is available for immediate reuptake by the post-ganglionic nerve endings in order to kick our bodies into high gear to react rapidly if need be. The heart is pumping to ensure the body gets adequate blood flow. In primitive times, you will need your muscles to outrun that cougar. The blood vessels constrict within the organs to make blood flow more available to the muscles necessary for running. Blood flow is shunted to the liver to make energy stores more available. The pupils dilate so they widen allowing more light and you can see your surroundings better in dark light. The breathing becomes heavier because you will need more oxygen when you try to outrun that crouching cheetah in the jungle.
It is a primitive response so engrained in our system that we cannot ignore or control it. The palms sweat, well, because that’s part of the sympathetic nervous system. Sweating allows you to cool off in hot temperature. If you run hard and fast you become hot, you need sweat to cool down. It is essentially a primitive response entrenched within our systems that help you react towards an untoward situation. By the same token, animals must sometimes freeze in the jungle so they are not seen and eaten by large predators. This is similar to the evolutionary freezing we feel when we are involved in a potentially dangerous situation and suddenly stop and do not know what to do.
However, everything is interrelated. It is not just the fear of the unknown or being in an unusual situation that can trigger this response. Our memories and emotions may trigger the sympathetic nervous system. Say you walk into a business deal that is supposed to be mutually beneficial. You have high hopes for a great outcome. You walk into the conference room, look your interviewer in the eye and shake his hand. This person is unusually cheerful and accommodating. You are just happy to have someone interview you in the location of your choice. However, as you start to listen to the situation your mind is triggered by statements that harken back to a situation in a previous job from which you suffered burnout. They are way too accommodating but little statements are voiced making you wonder about the real situation and why they are being a little too nice and too happy about an overburdened schedule. This is where the hippocampal cells in the temporal lobe come in to subserve their function with learned memory. Your amygdala is processing everything emotionally connecting the dots. While logic is saying take the job it is an ideal location, the salary is great, your amygdala is dissecting emotional content in the discourse and on facial features. It picks up on any fallacy when emotions and statements do not coincide. You detect a disconnect between the sunny disposition and the weight of the job. The intuition many people opine about is really the primitive amygdala telling you when something is not quite right. It detects the unsaid component of a situation and ultimately determines your next course of action. While you are about to start the job your amygdala is screaming out to you releasing hormones producing a milder version of the fight or flight response veering you away from a potentially stressful situation and giving you a completely different reaction from what logic would determine. You feel stressed every time you think about your first day at work. The heart beats a little more quickly, it is a milder version of the sympathetic response found in fight or flight but essentially your amygdala is activating your system to respond as you do in an adverse situation.
The same is true when encountering the threatening looking person. You have an idea they are up to no good, looking shiftily away darting their eyes back and forth. Your brain registers something adverse is about to go down. It’s not paranoia, it’s your primitive brain the amygdala picking up on suspicious activities steering you towards a reaction towards a potentially adverse event.
Therefore, when your spidey senses tingle, it’s not intuition, it’s not a sixth sense or premonition. It is cerebrally mediated with your primitive brain steering your emotional component to wind your body up about to react to a stressful situation. At one end of the spectrum, it is the fight or flight response at the milder end of the spectrum it is the stress you feel when you are about to make a big mistake. The axiom is true, listen to your gut, to be more apt listen to your amygdala masquerading as your spidey senses.
When the hair on the back of your neck tingles, listen to those spidey senses.
Neurology Buzz 