medical marijuana

Cannabinoids: the other side of the coin, side effects, drug-drug interaction and possible problems of cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D., Board-Certified Neurologist, Epileptologist

@VThornleyMD

April 6, 2018

 

Introduction

Medical marijuana seems like the shining breakthrough drug the shining pill in armor, the magic pill that seems to cure everything. However, there are always two sides to every coin. One must still proceed with caution. The phytocannabinoids, cannabidiol, and tetrahydrocannabinol exert their effects through the endocannabinoid pathway, the CB1 receptor is most abundantly found in the nervous system. Cannabidiol which has no euphoria acts weakly with the CB1 receptor almost as a reverse agonist blocking the THC from exerting its effect offsetting potent side effects of tetrahydrocannabinol.

The medical benefits are overwhelmingly numerous including ameliorating seizures, spasms from multiple sclerosis, peripheral neuropathy in HIV patients, chronic debilitating pain, post-traumatic stress disorder symptoms and other associated diseases. Despite the stigma of using it, the delay in clinical trials and marked hesitation of the medical community, medical marijuana has landed and there is no going back. Yet even with its numerous health benefits, it is always prudent to take a step back and examine any flaws as with any other new kid on the block or any new agent that comes along even though it’s been around for thousands of years.

Is marijuana safe for medical use? The take on medical marijuana by the FDA

So far from the FDA official website, the FDA does not recognize medical marijuana coming from the botanical plant with any medical indication. The FDA does not recognize it to be safe or beneficial for any type of disease or condition. The FDA will facilitate any companies interested in bringing quality products including science-based research. The full take of the FDA on marijuana can be found here https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#use

Long-term effects on the brain

Perusing the scientific literature, it is difficult to find any long-term damage to the brain. There was a report in a heavy marijuana user where there was damage to the corpus callosum, possibly worse with young users (1). This is a small study of 11 heavy marijuana users with 11 age-matched cohorts. Diffusion tensor imaging was used. Previous reports alluded towards poor cognition with heavy marijuana use. This study is aligned with that. It was suggested that there may be increased diffusibility within the white matter tracts of the corpus callosum. Young age is thought to make the corpus more susceptible to white matter damage. The only caveat is this is with heavy use and the substance found in recreational marijuana is going to be a different form compared to medical marijuana extracted from the marijuana plant used for medicinal purposes. It is not clear if this report would carry over to medical marijuana users where the preparation of the product is much different(1).

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Effect on schizophrenia spectrum diseases

In a large study of 171 patients, it was found that with heavy use of cannabis, the age of onset of schizophrenia spectrum disorders seems to occur earlier (6). This is one of the reasons why in some dispensaries, it is not sold to patients with a history of schizophrenia. There are some anecdotal reports of some patients having a paranoia with medical marijuana that is reversible once taken off.

Effect on the heart, reports of myocardial infarcts and ST elevations

While the literature suggests low toxicity and most side effects are related to cognition and gastrointestinal problems, there are several cannabis-associated myocardial infarcts in the literature. The dispensaries in the state of Florida use a previous history of a previous myocardial infarct as a contraindication in using medical marijuana. These were synthetic drugs used recreationally. There was one case report where a heavy user suffered from an ST elevation and subsequent myocardial infarct after becoming toxic to marijuana used recreationally.  In one study, synthetic cannabis was used, the myocardial happened to a young patient where an atheromatous plaque was excluded as the source. Etiology and mechanism are unclear why infarcts should occur. It is quite possible that because it works on the 5HT receptor for anxiety which can cause vasoconstriction, this may be one mechanism. Other studies are needed to elucidate the mechanism of action.

Drug-drug interactions

Because medical marijuana is used as an adjunctive agent for epilepsy, perhaps off-label since it has not been approved through FDA as an anti-epileptic agent yet, it was found that medical marijuana used in conjunction with Clobazam (Onfi) tended to elevate Onfi at higher levels.

In one small clinical study, in 13 patients, 9 had an increase of about 60 in the Clobazam level and by 300 in Norclobazam level. There was, however, a tremendous reduction of seizures by >50% but Onfi (Clobazam and Norclobazam levels) should be monitored (3) on a routine basis to avoid any untoward toxicity.

Other milder symptoms

In one large study on Lennox-Gastaut syndrome where cannabidiol was titrated to a 20mg/kg over a course of 14 weeks, mild to moderate symptoms were noted including pyrexia, sedation, dizziness, and diarrhea. However, the titration rate was very rapid and the patents who were 50kg were quickly at 1000mg within 14 weeks which does not usually happen in the real world. Medications are usually increased over a longer period of time in slower increments.

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In summary

While everybody is touting the horn of medical marijuana it is always prudent to stand back and ensure there are no possible risk factors for adverse side effects. The most serious and common seen in the literature appear to be related to schizophrenia spectrum disorders and cannabis associated myocardial infarct. The only caveat is that the literature is peppered with these reports, however, the quality of the recreational drugs are vastly different from medical marijuana which tends to be organic and all natural extracted from the plant in licensed medical dispensaries. The extraction of the medical components is vastly different from the smoked synthetic version of tetrahydrocannabinol. So, is difficult to know if these reports would actually corroborate with use in medical marijuana. The ones with side effects were heavy users of recreational smoked types of marijuana, it is unclear if it was synthetic or organic. As the popularity of medical marijuana progresses, more information will be available regarding the side effect profile.

References

  1. Arnone, et al, “Corpus callosum damage in heavy use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics,” Neuroimage, 2008, Jul., 1, 41 (3): 1067-74.  “J Addict Med. 2017 Sep/Oct;11(5):405-407. doi: 10.1097/ADM.0000000000000326.
  2. Volpon, et al, “Multiple cerebral infarcts in a young patient associated with marijuana use, ” Journ. Addic. Med, 2017, Sep./Oct., 11(5):405-407.
  3. Geffrey, Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy,” Epilepsia, 2015, Aug., 58 (8):1246-1251.
  4. Stewart, et al, “Obstructive sleep apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones,” Epilepsia, 2017, Jun., 58(6): e87-90
  5. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#use
  6. Shahzade, et al, “Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder,” Schizophrenia Research, 2018, Feb., 2 pii S090-9964 doi:10. 1016/j. schres. 2018.01.008 (Epub ahead of print)
  7. Orsini, et al, “Prolonged cardiac arrest complicating massive ST-segment elevation myocardial infarct associated with myocardial consumption,” J. Community Hosp. Intern. Med. Perspect, 2016, Sep., 7. 6 (4):31695
  8. 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

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Epilepsy

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).

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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.

https://neurologybuzz.com/

Introduction/Disclaimer

About

References

  1. Strong, et al, “Effect of trained seizure alert dogs on the frequency of tonic-clonic seizures,” Seizure, 2002, Sep., 11(6):402-405.
  2. Brown, et al, “Can seizure-alert dogs predict seizures?” Epilepsy Res., 2011, Dec., 97(3):236-242.
  3. Dalziel, et al, “Seizure-alert dogs: a review and preliminary study,” Seizure, 2003, Mar., 12 (2):115-120.
  4. Strong, et al, “Seizure alert dog-fact or fiction?”Seizures, 1999, Feb., 8 (1):62-65.
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Epilepsy

The deleterious effect of caffeine on epilepsy and anti-epileptic agents

Virginia Thornley, M.D., Neurologist, Epileptologist
March 25, 2019
Introduction
Caffeine (1,3,7-methylxantine) is one of the most commonly ingested stimulants in the world. It is not uncommon for someone to ingest a daily consumption of 200mg of caffeine a day. It is ubiquitously found in soda, coffee, tea, and chocolate. It is the bane of every neurologist who treats migraine and patients with insomnia. It acts as a stimulant and many people use it to counter fatigue induced by lack of sleep. Students consume it to stay up at night for late night studying in order to ace their tests the next day. Millions of people ingest caffeine on a regular basis to get through the full work day.
Caffeine worsen seizures
It has been found in animal models to lower the seizure threshold. At low doses, it reduces the efficacy of anti-epileptic agents. At more than 400mg of caffeine per day, in rodent models it is found to induce seizures. In experimental data, use of caffeine is found to lower the seizure threshold. In mouse models, at lower doses below the seizure-inducing effects, it is found to counter the protective beneficial effects of anti-epileptic agents such as carbamazepine, phenytoin, valproate, and phenobarbital as well as newer agents such as topiramate.  There seems to be no effect of caffeine on newer agents such as tiagabine, oxcarbazepine or lamotrigine. There is clinical data confirming that ingesting high doses of caffeine correlates with greater number of seizures.
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Dark cocoa and seizures
Dark chocolate is also found to be a proconvulsant, but little is known about the mechanism of action. Dark chocolate is rich in caffeine. In one mouse study, the effect of high intake of dark chocolate on the susceptibility of hippocampal cells to seizures was examined. Dark cocoa appeared not to affect mood behavior but improved motor coordination.  However, electrophysiologic studies showed enhancement of bursts of epileptogenic potential within the dentate gyrus of the hippocampus. There was a reduction in GABA-alpha receptors suggesting that consumption of dark chocolate may alter the synaptic aspect of epileptogenesis in the temporal lobe.
These findings suggest that high consumption of caffeine especially dark cocoa can increase seizure frequency in animal models and in clinical studies. It seems to act as a proconvulsant and reduces receptors that are necessary for inhibiting seizures.
Reference
  1. Chroscinska-Krawzyk, et al, “Caffeine and anticonvulsant potency of anti-epileptic drugs: experimental and clinical data,” Pharmacol. Rep., 2011, 63(1):12-18.
  2. 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.
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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.

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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.

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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.

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Introduction/Disclaimer

References:

  1. 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.
  2. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
  3. 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.
  4. 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.
  5. 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.
  6. Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
  7. 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.
  8. 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.
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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.

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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.

About

Introduction/Disclaimer

https://neurologybuzz.com/

References

  1. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
  2. 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.
  3. Gaston, et al, “Pharmacology of cannabinoids in the treatment of epilepsy,” Epilepsy Behavior, 2017, May, 70(Pt B):313-318.

 

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