Medical Practice

Understanding the practical aspects of cannabidiol (CBD) and tetrahydrocannabinol (THC)

 

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

@VThornleyMD

July 15, 2018

Introduction 

This serves as medical information for educational purposes only not medical advice. Please consult with your treating  physician.

In contrast to the rest of the blog which is more scientific, this gives more practical information in the day to day workings of recommending medical cannabis. It gives the behind the scenes processes that happens before a patient can even begin to start their medical product. It is not a magic pill but because it is unlawful in Florida, a physician cannot even write it on a prescription pad. It takes one hour or more to evaluate, counsel and go over the registration process when presenting for the first time to a doctor.

For more detailed information and scientific references for specific indications please refer to
https://neurologybuzz.com/

Medical cannabis is one of the most misunderstood and controversial medications in the world. Long suppressed for over a century, it is one of the most misunderstood medications known to mankind despite being used for thousands of years with medical intent.

 

This is to give a brief basic background of mechanisms, rationale for ratios, combinations, pitfalls of isolates and synthetics and legal implications.

Background

Very briefly, the endocannabinoid system is found naturally in our body. It is responsible for the runner’s high people get. It gives a sense of wellbeing, not endorphins like most people think, those molecules are too large to pass the blood brain barrier. There are 2 receptors:(1) the CB1 receptor found mostly in the nervous system and (2) the CB2 receptor which is more abundantly found in the immune system. Anandamide works on the CB1 receptor, Tetrahydrocannabinol (THC) is similar to this and works on the CB1 receptor. CBD or cannabidiol is from the cannabis sativa plant and is also a cannabinoid. One needs 100 times CBD to get the same euphoria as THC. CBD is not intoxicating, legal and works on a wide variety of symptoms including pain, seizures and anxiety. CBD is similar to 2-arachidonoyl glycerol which is a natural cannabinoid. When you combine the 2 together, CBD will offset side effects of THC including paranoia, hyperactivity and agitation. This is a little known fact to those who self medicate.https://neurologybuzz.com/2018/04/02/medical-marijuana-vlog-series-part-i-mechanisms-medical-benefits-of-non-intoxicating-cannabidiol-and-tetrahydrocannabinol/

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Pitfalls of self-medication

When patients self-medicate and use pure THC to alleviate symptoms, there are intoxicating effects which are not seen when recommended medically using oral forms, cream or patch. At low doses, as is done when recommended medically, THC is non-euphoric. When THC is combined with CBD the side effects of THC are offset. The dangers of patients who self-medicate is that they do not know where the products are coming from and it can be mixed with potentially dangerous substances that can be potentially fatal. In addition, there are highly potent synthetic illegal cannabinoids known as K2 and spice which at high doses can cause cardiotoxicity and fatalities. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

Why is a CBD and THC combination important?

In regulated licensed dispensaries, CBD is combined to offset the side effects of THC making it better tolerated. This concept is not well-known to the public or the medical community. The stigma is still strong. THC is not recommended by itself because of side effects including paranoia, agitation and hyperactivity. Within the nursery farm, the strains of the cannabis sativa plants are grown at a certain temperature under a certain amount of sunlight. It is strictly controlled so that different strains are produced.

 

CBD by itself

With pure CBD, there are certain medical symptoms that are alleviated better than combination CBD:THC.

It is legal. There are many companies with CBD products but it is difficult to know how pure these products are, even if you have a small amount of hemp it can be marketed as CBD hence, its ineffectiveness. Some of the most effective CBD products can be found from Colorado and California, just anecdotally. Everything else will be hit or miss.

In the state of Florida, there are very few medically beneficial CBD products, it’s trial and error. The purer the form such as full spectrum CBD oil the more expensive it will be because processing organic products are costly. A cheap product will likely not be as pure just because of the huge amount of work that goes into extracting the cannabidiol. In addition, some may have flavors, cutting agents and other agents to dilute it but because it’s unregulated it is not disclosed.

Ratios

CBD alone has no psychoactivity but medical value. CBD must be combined with THC in order to offset its side effects of paranoia, agitation and hyperactivity. The lowest ratio is 1:1 ratio which covers a wide variety of symptoms. The ratios increase incrementally 1:4, 1:9, 1:20, 1:80, 1:90. The higher ratios are reserved for the terminally ill as it can cause greater amounts of side effects. Higher ratios of THC achieves greater pain relief. Higher ratios of CBD help with anxiety but can also help with pain and seizures. Dosages and ratios should be low then increased incrementally by the week to see the best effect. https://neurologybuzz.com/2018/04/04/part-iii-medical-marijuana-video-series-vlog-different-combinations-and-ratios-of-cannabidiol-and-tetrahydrocannabinol-and-indications/

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Time of onset and duration

There are different ways of trying it: vaporizer lasts 1 hour and takes about 10 minutes to get into your system. Because the vaporizer is inhaled into the lungs the onset is the fastest because of the rich supply of blood vessels in the lungs. It is advisable to try the vaporizer at home or at night before setting out to see how it affects you. Oral forms last 6 to 7 hours and takes about 1/2 hour to get into your system. Oral form comes in oil concentrate and tincture. Cream and patch last about 12 hours or longer depending on the preparation. Medical marijuana is NOT recommended by physicians to be smoked. Recreational marijuana by smoking is prohibited and unlawful in Florida. This law varies by state. When different parts of the plant are taken together including the terpenes it gives an entourage effect which is more medically valuable than when components are isolated for its use.https://youtu.be/Ir4rwgF2iNc

Are there any edibles in Florida?

As of July 2018, there are no edibles in the state of Florida. It will take an enormous amount of applying, submitting documentation and providing capital before edibles will be implemented in Florida. The dispensaries are working on this.

 

Registration process: what to expect in Florida

The process includes an evaluation by a qualified licensed physician. https://neurologybuzz.com/2018/07/12/legalities-and-application-process-in-the-state-of-florida/A qualified physician undergoes a 2-hour course and holds a full medical license in the state of Florida. One is evaluated and if  patient meets the stringent criteria, they obtain a registry number. The patient will undergo a registration process which takes between 2-4 weeks. An email arrives before the card then one is instructed to call the office so that recommendations are placed in the system. Oftentimes, if you don’t hear back in 4 weeks it is advisable to give the registry a call. It may be a misenetering of an e-mail causing a hold-up.

Regulated dispensaries in the Florida

In Florida state there are 13 medical marijuana treatment centers and 43 retail dispensaries as of July 2018. In the state of Florida, patients can only obtain the Cannabis products recommended from their treating physicians from these dispensaries. It is illegal to smoke. There are 4 ways of taking it: oral, vaporizer, cream and patch. It is advisable to visit one of the licensed dispensaries in person so that the exact instructions can be given. Physicians recommend orders which are entered into the system. So long as the product is within the number of mg dispensed and the way it is recommended (oral, vaporizer, cream or patch) patients are at the liberty to change the ratio or dosage so long as it is within the orders.

 

Once you are registered

An e-mail with the marijuana card number comes before the physical card. It is advisable to call the physician office so the orders are placed then physically visit the dispensary of your choice so specific instructions can be taken. Because this is not a pharmacy, doctors do not have immediate access to the dispensary. One should be aware of which product they are taking before their next checkup. This can be easily accessed through the website of the dispensary.

The orders will expire after 70 days after which there is a processing fee of renewal at our office. The certification for medical marijuana expires after 1 year. One must be re-evaluated by their physician before then.

CBD is purely cannabidiol, it is non-psychoactive and legal. THC at low doses is non-intoxicating. Dispensaries combine CBD and THC to offset side effects.  It is federally illegal. It is advisable to be registered under a medical doctor who is qualified to determine if one meets criteria. Medical cannabis products can only be dispensed from a regulated licensed dispensary. Medical marijuana products outside of the jurisdiction of Florida regulates licensed dispensaries cannot be advocated.

Legal implications of THC

In some states, such as Florida, medical use of cannabis is recognized. THC is still considered federally illegal. Recreational use of cannabis is illegal. Smoking THC is illegal. Physicians cannot prescribe it since it is a schedule 1 drug but can recommend it. Schedule 1 drugs are considered illicit and labeled as having no medical use.

In other states, medical and recreational use is allowed.

In other states, medical and recreational use is completely banned.

The law also varies regarding cultivation of the cannabis sativa plant.

Countries will vary in their marijuana laws.

The laws change very rapidly. Regulations are changed nearly every month with more documentation required from physician offices including consent, doctors’ notes, patient information with indication. As each month goes by another new document is required for submission from the physician office. There is increasing bureaucracy likely signifying resistance at some upper levels against its use related to economic and political reasons. Dispensaries have an equally challenging time. Even worse are small farms applying for licenses huge amounts of capital and documents are required.

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Legal implications of CBD

CBD is legal throughout the US. Countries may vary in their laws since they both come from the cannabis sativa plant.

FDA approved medications and products approved in Europe with CBD and THC

A medication called Epidiolex for seizures with CBD has recently been approved for seizures. Because it comes from a strain from the cannabis sativa plant, cannabis will need to be deregulated from the schedule I category before Epidiolex can be marketed to the public.

Dronabinol has long been approved for nausea and can only prescribed for patients with cancer with chemotherapy induced nausea. It is a synthetic THC and is FDA approved.

In Europe, the medication Sativex which is a combination of CBD:THC has long been used for spasms in multiple sclerosis. This is not available in the US.

In summary

For patients, it is beneficial to have a working understanding of the different strains, different forms that are available in order to obtain the best benefit.  Dispensaries have a huge breadth of products. It is easier to understand as much as possible before facing the overwhelming number of options. Patients must understand all the legal implications in your state as they change rapidly. It is not only a medication it is affected by state and federal laws that change in a blink of an eye which can affect the patient if they are not aware.

For doctors recommending, one must be well-versed in understanding the ratios, the combinations, the potential side effects, drug interactions, the latest scientific research since these are the only guidelines that are guiding us from a scientific level. Pre-clinical studies cannot be ignored nor studies on synthetics to have a better grasp of understanding how it works. One must have a basic understanding in the relationship of the different strains, effects on each other, entourage and synergistic effects of the phytocannabinoids taken in combination and not in isolation. Patients come with complex medical problems it is always prudent to do due diligence in understanding as much as possible before recommending a product that was never studied for medical purposes in medical school. Patients will ask tough questions, physicians should understand as much as possible and do their homework being up to date on legislations as well as the most recent research.

One must also follow the legal implications, current regulations which are frequently updated. It is the physician’s responsibility to understand the mechanisms, be up to date on the literature because this is a pioneering science. Those recommending right now are trailblazing and should still be mindful of the great role you play in understanding what literature is available and to read voraciously.

Last thoughts

While much is still unknown about CBD, THC and mechanisms, there is great anecdotal data from history and clinical anecdotal experience supporting its benefits. While many traditionally trained physicians scoff at the prospect of introducing alternative treatments, one must bear in mind cannabis was not an alternative medication before it was banned in 1830.

While scientists are working overtime in elucidating the mechanisms to combat diseases such as cancer, one must bear in mind that medical cannabis is beneficial when taken in combination with other terpenes found in the plant and the components are not isolated from each other. THC works best in combination with CBD and with other components from the cannabis sativa plant.

When components are isolated from each other and products become synthetic and manufactured much of the benefits are lost and significant side effects result. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

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Once it becomes synthetic and components are isolated, the benefits will be substantially altered.

 

Now is a optimal time to try the benefits of medical cannabis while it is still all organic and being produced on farms and regulated for its use, unsullied by synthetic forms where the risk of side effects are greater.

While much is still to be learned, for a medicine that can easily cover 5 symptoms in one setting, it is an extraordinary time to be recommending and benefiting from medical cannabis while it is still organically natural and pure.

 

Introduction/Disclaimer

About

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Cancer research and cannabinoids

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

Virginia Thornley, M.D., Neurologist, Epileptologist

June 24, 2018

@VThornleyMD

https://neurologybuzz.com/

Introduction

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

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

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

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Endocannabinoid system

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

Endocannabinoids and the role in cancer

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

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

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

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

Effect on tumor cells

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

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

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

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

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

In summary

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

References

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

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

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

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

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

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fibromyalgia

Medical marijuana in fibromyalgia: molecular mechanisms and small randomized controlled trials

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

June 17, 2018

Introduction

Fibromyalgia used to be  a condition denoting excessive pain and was previously questionable as there was no testing that could prove or disprove it. Now, the current thought is that it is attributed to hypersensitivity of the nervous system to pain impulses resulting in multiple points of pain in the body.

Endocannabinoid system in pain modulation

The endocannabinoid system is a major chemical neurotransmitter system that has only come to light as to physiology in the last 20 years. The CB1 receptor is found predominantly in the nervous system on which the endogenous endocannabinoid anandamide exerts its effects. The CB2 receptor is found mostly in the immune system on which 2-Arachidonoylglycerol acts. In the nervous system, cannabinoid receptors are seen in the periaqueductal gray area, ventromedial medulla and dorsal horn of the spinal cord which are areas where pain transmission takes place. This suggests that endocannabinoids play a major role in modulation of pain and can impact pain control through manipulation of this system.

Anandamide and and 2-Arachidonoylglycerol are synthesized on demand. It is released immediately after production. 2-AG is formed from a 2 step process. Anandamide has a low affinity to the TPRV1 receptor (2).

1,2-diacylglycerol (DAG) is  a precursor or 2-AG which is formed by hydrolysis of membrane phosphoinositides. DAG is hydrolyzed by 2-AG hydrolase to form 2-AG. 2-AG may be stimulated by activation of G protein receptor such as glutamate receptors. It activates both CB1 and CB2 receptors. Cannabidiol which is found in the cannabis sativa plant is a natural mimetic of 2-AG. Endogenous 2-AG is found 170 times more than Anandamide in the brain. Exogenous 2-AG suppresses nociceptive stimulus (2). 2-AG activity is potentiated with natural 2-acylglycerols which enhances the effects which does not happen when used alone. This is an entourage effect found in the brain where the combination of substances give a combined resulting effect which does not occur if used alone (2).

Mechanisms in pain modulation

Cannabinoids were found to reduce nociceptive transmission at the level of the pain c-fiber responses in the spinal dorsal horn.

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Randomized controlled trial in fibromyalgia

In one study of 40 patients in a randomized controlled clinical trial, nabilone which is a synthetic cannabinoid was given over a 4 week period. Measures that were evaluated included the visual analog scale for primary outcome and for secondary outcome measure, tender points, secondary outcome measure, Fibromyalgia Impact Questionnaire (FIQ) at weeks 2 and 4 were used. There was statistical difference in treated vs. control groups for pain (P value< 0.02), anxiety (P<0.02 and FIQ (P<0.02). There were more side effects for the treated cohort compared tot he placebo controlled group. This study demonstrates that cannabinoids may be an effective treatment for fibromyalgia (1).

In one paper that reviewed 18 randomized controlled clinical trials of cannabinoids in chronic pain syndromes including fibromyalgia, cannabinoids were found to be an effective type of treatment. Despite the short duration of the trials, pain relief was effective and mild to moderate adverse effects were noted. Larger clinical trials are needed (2).

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  1. Skrabek, et al, “Nabilone for the treatment of pain in fibromyalgia,” J. Pain, 2008, Feb., (9)2:164:173
  2. Lynch, et al, “Cannabinoids for treatment of chronic non-cancer pain: a systemic review of randomized trials,” Br. J. Pharmacology, 2011, Nov., 72(5):735-744
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obsessive compulsive disorder

Cannabinoids in obsessive-compulsive disorder: mechanisms and effectiveness in the animal model

Virginia Thornley, M.D., Neurologist, Epileptologist

June 16, 2018

Introduction

Obsessive-compulsive disorder infamously known to the layman as someone who is excessively interested in keeping their environment clean and orderly. It is a neuropsychiatric condition, where thoughts or actions are repetitive. Usually it involves the complex balance of neurotransmitters within the nervous system so that ideas and actions are carried out in a specific manner. When there is an alteration, repetitive loops occur resulting in repetitive thoughts or reverberating loops of motor activity without the usual negative feedback inhibition. Clinically, this results in intrusive thoughts and repetitive actions that are difficult to control.

Because there is a fine orchestration of the interplay of neurotransmitters, many psychiatric agents have been developed  but success is not always complete.

Medical cannabis is emerging as a treatment option recognized as successfully treating many neuropsychiatric conditions. While large clinical randomized controlled trials are sorely lacking. Scientific research is also necessary to understand the exact science on why t might help with neuropsychiatric disorders.

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Mechanisms of cannabinoids on the CB1 receptor to alleviate repetitive behavior

Anandamide and 2-AG are metabolized by FAAH or fatty acid amide hydrolase and MAGL or monoacyglycerol lipase. FAAH inhibition has been shown to increase anxiolytic effects of endocannabinoid anandamide.

One study sought to seek the effects of FAAH inhibition and MAGL inhibition on the marble burying features of mice (1). Marble burying is a research measure where marble burying is thought to be a sign of anxiety in animals and may correlate with compulsive behavior in mice to alleviate anxiety. Marble burying is an acceptable animal model to demonstrate repetitive behavior and anxiety elicited from mice demonstrating obsessive compulsive disorder (2). Marble burying is not affected by the novelty of the marble or by anxiety. Marble burying is suggested to be a repetitive perseverative type of activity related to digging movements of mice and is a valuable measure in research to evaluate repetitive responses in animals (2).

Benzodiazepines, PF-3845, an FAAH inhibitor and JZL184, a MAGL were found to reduce marble burying activity but did not affect locomotor activity. Delta-9-THC did not reduce marble burying behavior without reducing the locomotor activity (1). In essence, there was significant hypomotility with the marble burying activity.

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Reduction of catabolic enyzymes of endocannabinoids may alleviate anxiety

An antogonist at the CB1 receptor negated the reduction of marble burying activity of FAAH and MAGL but not the benzodiazepine. This suggests that the CB1 receptor has anxiolytic properties. Possible treatments would include targeting of the enzymes that break down cannabinoids making the cannabinoids more available.

Cannabidiol effect on obsessive compulsive behavior in the animal model

Cannabidiol was given to mice using the marble burying test which is an animal model demonstrating compulsive behavior. At 15, 30 and 60mg/kg there was effective reduction of marble burying behavior compared to control mice. This study demonstrated that cannabidiol is effective in reducing repetitive perseverative behavior similar to the conditions in obsessive compulsive disorder (3).

In summary

While most of the preliminary data is entirely preclinical, there is scientific evidence that cannabidiol can reduce obsessive-compulsive behavior in the animal model. The mechanism appears to be at the level of the CB1 receptor. While preclinical data does not always translate into positive human results, this concept is promising. Clinical studies are needed.

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Reference

  1. Kinsey, et al, “Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay,” Pharmacol. Biochem. Behav., 2011 Mar, 98(1)21-7
  2. Thomas, et al, “Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety,” Psychopharmacology, 2010, Jun., 204(2):361-373
  3. Casarotto, et al, “Cannabidiol inhibitory effect on marble-burying behavior:involvement of CB1 receptor,” Behav. Pharmacol, 2010, Jul., 21(4):353-358
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cannabidiol, Epilepsy

Scientific and clinical evidence of cannabidiol (CBD) and seizure control: mechanisms, randomized controlled clinical trials, open label trials and animal models

Virginia Thornley, M.D., Neurologist, Epileptologist 

@VThornleyMD

May 22, 2018

Introduction

There are numerous scientific studies that have studied the effect of cannabidiol by itself on seizure control encompassing animal models, longitudinal observational studies, case series and currently randomized double-blinded placebo-controlled clinical trials. It is difficult to ignore the wealth of information regarding the medical value of cannabidiol with a significant role in the treatment of epilepsy.

The endocannabinoid pathway and cannabinoids

The endocannabinoid pathway is found naturally within our system, comprising of receptors, transporters, and endocannabinoids. It is responsible for the sense of well-being one gets after running referred to as the “runner’s high,” and not endorphins, serotonin or noradrenergic neurotransmitters as their molecular sizes are too large to pass through the blood-brain barrier. There are 2 types of receptors, CB1 and CB2 receptors. CB1 is found predominantly within the nervous system and is the receptor on which tetrahydrocannabinol works and it is through this binding where psychoactive properties arise. There are two metabolites within the endocannabinoid pathway, anandamide for which tetrahydrocannabinol (THC) is a phytomimetic and 2-arachidonoyl-glycerol for which cannabidiol is a phytomimetic. Cannabidiol (CBD) acts as an inverse agonist on the CB1 receptor, with a weak affinity. 100 times of cannabidiol is needed to get the same psychoactive properties as tetrahydrocannabinol. When CBD is combined with THC the side effects of paranoia, hyperactivity and agitation become less because it is an inverse agonist of the CB1 receptor. In many animal studies, cannabidiol has anti-inflammatory, anti-oxidative and neuroprotective actions within the nervous system (8).

Mechanisms by which cannabidiol works 

It is thought to modulate the neurotransmitter system. Endocannabinoids are increased as a result if hyperexcitability in the nervous system. CBD can regulate intracellular calcium during hyperexcitability states in the hippocampus in the temporal lobe. CBD can regulate NMDA (N-methyl-D-aspartate) receptor transmission and increase serotonergic 5HT-1A (5-hydroxytryptamine)receptor transmission and reduces GABA, 5-HT1A, and norepinephrine synaptic uptake (9). Cannabidiol is thought to be neuroprotective through its role in controlling intracellular calcium. Excess calcium can activate a cascade of neurochemical events leading to cell degeneration and death through lipases, endonucleases, and proteases. In one study in rat models, there was a suggestion that treatment of seizures was not just at the neurotransmitter level but also modulates the oscillatory nature, neuronal loss and post-ictal lethargy of the status epilepticus model.

Scientific evidence in animal models

Animal studies show that the effectiveness of cannabis is at the level of the CB1 receptor. With the deletion of the CB1 receptors in the forebrain excitatory neurons in the mice model, Kainate-induced seizures were more prominent. The presence of CB1 receptors in the hippocampal gyrus seems to protect against Kainate-induced seizures. Viral-induced CB1 overexpression resulted in less Kainate-induced seizures, CA pyramidal cell 3 cell death. This demonstrates that the presence of the CB1 receptor can limit seizures and reduces gliosis and apoptosis (4).

 

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In animal studies, the CB1 receptors increased 1 week after pilocarpine-induced seizures in the CA1-3 striatum oriens and the dentate gyrus. Patients with temporal lobe epilepsy had reduced Anandamide and increased CB1 receptors suggesting an up-regulation of the CB1 receptor as a homeostatic mechanism in the presence of seizures which can reduce excitatory neurotransmitters (4). This compensatory mechanism may be impaired with long-standing seizures and hippocampal sclerosis and refractoriness to pharmacologic measures.

Case series report

In a small study on patients with tumors with seizures, in 3 patients who were medically refractory were started on cannabidiol (Epidiolex) to treat seizures. 2 out of the 3 had improvement in seizures while all 3 had improvement in the severity in the University of Alabama (2).

Evidence in longitudinal observational studies

In one study of 57 patients, ages 1-20 years old, CBD:THC was given at a ratio of 20:1 with the CBD component of 11.4 mg/kg/day. The patients were followed longitudinally for 3 months with a follow-up time of 18 months. 56% or 26 patients had <50% reduction of seizures. No difference was noted between the causes of the seizure and the type of cannabis used. Younger ages of 10 years old and below had a statistically better outcome compared to an older age. Those with higher doses of CBD of >11.4mg/kg/day had a statistically better outcome compared to 11.4mg/kg/day and below. There were side effects in about 46% of patients leading to stopping the protocol. These studies suggest that cannabidiol enriched treatment may be beneficial in seizure control particularly in the pediatric population.  (1).

Open-label studies

In an open-label trial, 214 patients were studied between the ages 1-30, with pharmacoresistant epilepsy. There were 162 in the safety follow-up of 12 weeks, 137 were in the efficacy analysis. For the safety group, 33 had Dravet syndrome and 31 had Lennox-Gastaut syndrome. The rest had medically refractory seizures from different causes. Side effects were mild to moderate including diarrhea, lack of appetite, somnolence, fatigue, and convulsion. 5 had a cessation of treatment related to adverse effects. Serious events were reported in 48 patients with 1 death unrelated to cannabidiol. 20 had severe adverse effect including status epilepticus. The median number of seizures at baseline was 30 which was reduced to 15 per month with a 36.5% reduction of motor seizures (7).

Evidence in randomized controlled clinical trials 

In a multi-country study was performed on Dravet syndrome and effect of cannabidiol in a randomized double-blind trial of cannabidiol versus placebo and in young adults between the ages of 2-18. Dravet syndrome is an epileptic syndrome involving myoclonic epilepsy during childhood which may progress attributed to an SCN1A gene abnormality. There was a 4 week baseline period followed by a 14 week treatment period. The dosages of cannabidiol were increased gradually to 20mg/kg/day. Those in the cannabidiol group was matched to a placebo control. The endpoints were the percentage of change and Caregiver Global Impression of Change (CGIC). In 23 center in the U.S. and in Europe, 120 patients underwent randomization, mean age was 9.8 years old. 108 completed treatment. The median number of drugs was 3 and the most commonly taken were clobazam, valproate, stiripentol, levetiracetam, and topiramate. The most common type of seizures was generalized tonic-clonic followed by secondary generalized tonic-clonic seizures. 114/118 children presented with developmental delay. Adverse reactions were mild to moderate including somnolence, diarrhea and loss of appetite. Elevated liver enzymes were found in those taking valproate likely related to drug-drug interactions. The reduction of seizures was considered meaningful while no change in non-convulsive episodes was noted. In the cannabidiol group, convulsive seizures reduced from 12.4 seizures to 5.9 per month while the placebo control group had a reduction of seizures from 14.9 to 14.1 which was not statistically significant. A reduction of more than 50% of seizures occurred in 43% of patients in the cannabidiol group and 27% in the control cohort. 3 patients in the cannabidiol group and no one in the placebo group became free of seizures. 62% of caregivers thought the condition improved in the cannabidiol group as opposed to 34% in the placebo group (5).

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Another randomized placebo-controlled trial in Lennox-Gastaut syndrome was done using cannabidiol versus placebo. Lennox-Gastaut Syndrome is characterized by multiple seizure types with a slow spike and wave of 2.5 Hz or slower on EEG.  This study covered 30 clinical trial centers between the ages 2-55 with 2 or more seizures per week over 28 days. 225 patients were randomized with 76 in the group for cannabidiol at 20mg/kg/day, 73 in the cannabidiol group at 10mg/kg/day and 76 in the placebo cohort. The reduction in median of drop attacks was 41.9% in the 20mg cannabidiol group, 37% in the 10mg cannabidiol group and 17.2% in the placebo group which was statistically significant. Side effects were somnolence, diarrhea and poor appetite which was dose-related. 9% had higher liver function tests. The study concluded that addition of cannabidiol of either 10mg/kg/day or 20mg/kg/day in addition to standard anti-epileptic agents resulted in a significant reduction of seizures(6).

Cannabidiol as an add-on adjunct for refractory seizures

In another study in Slovenia, add-on cannabidiol was given to 66 patients who were deemed medically refractory at a dosage of 8mg/kg/day. 32 or 48% of patients experienced fewer seizures of more than 50% reduction. 14 (21%) were seizure free. No patient had to worsen and 15 or 22.7% there was no effect. Patients reported less robust seizures, less recovery time and less time duration of the seizures as positive outcomes. Adverse effects were seen in 5 patients or 0.07% of patients. They concluded that there are some beneficial effects of cannabidiol as an add-on adjunctive treatment in controlling medically refractory epilepsy(3). However, this study focused on cannabidiol as an adjunctive treatment, not as monotherapy.  Regardless, there are some beneficial aspects as evidenced in this study (3).

In summary

There is growing evidence that cannabidiol which is the non-psychoactive component of the Cannabis sativa plant is effective in treating intractable seizures, from the mouse model to randomized controlled clinical trials, which can no longer be ignored. There are mostly mild to moderate side effects involving the gastointestinal and neuropsychiatric system, although severe adverse outcomes include status epilepticus. There were no fatal outcomes associated with the use of cannabidiol. The real question are the long-term side effects and drug-drug interactions which can be studied once the cannabidiol is well-established as a conventional agent in the future.

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References:

  1. Hausman-Kedem, M., et al, “Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – an observational longitudinal study,” Brain Dev., 2018 Apr., pii:S0387-7604 (18)30112-8 doi: 10.1016/j.braindev2018.03.013. (Epub ahead of print)
  2. Warren, et al, “The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy,” Neurocase, 2017, Oct.-Dec., 23 (5-6):287-291.
  3. Neubauer, D., et al, “Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia,” Epilepsy Behav., 2018 Apr., 81:79-85. doi:10.1016/j.yebeh.2018.02.009. (Epub ahead of print)
  4. Rosenberg, et al, “Cannabinoids and epilepsy,” Neurotherapeutics, 2015, Oct., 12 (4):747-768.
  5. Devinsky, O., et al, “Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome,” New England Journal of Medicine, 2017, 376: 2011-2020.
  6. Devinsky, et al, “Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome,” NEJM, 2018, May,  378:1888-1897.
  7. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open label interventional trial,” Lancet Neurology, 2016, Mar., 15 (3):270-8.
  8. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  9. Do Val-da-Silva, et al, “Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy,” Front. Pharmacol., 2017, 8:131.
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