- Meehan-Atrash, J., Luo. W., McWhirter, K.J., Strongin, R.M. Aerosol gas-phase components from cannabis e-cigarettes and dabbing: mechanistic insight and quantitative risk analysis. ACS Omega. 2019, Sep. 16,;4(14):6111-16120
Virginia Thornley, M.D., Neurologist, Epileptologist
July 16, 2018
As medical marijuana emerges from the caves of obscurity in treating illnesses, physicians are at the forefront of rediscovering ailments that can be treated by medical cannabis. While most traditional scientists and trained clinicians do not think highly of anecdotal research, patients in clinical practice are the best parameters in judging whether a medication is working or not. Oftentimes, even with the best research, clinical practice conveys side effects that were never found during the short period of time of the study. Additionally, as hundreds of thousands of patients start using a new product it is only then one can observe the true efficacy and safety profile which accounts for why research does not always correlate with clinical practice.
Sometimes, one comes across a medication where certain other symptoms may be alleviated not listed on the indications. As a growing number of patients are recommended medical cannabis, they are presenting with a variety of symptoms that are incidentally relieved.
Background of endacannabinoids and relationship to areas in the brain subserving movement
One of the areas where the brain is rich in endocannabinoid receptors CB1 and CB2 receptors are in the basal ganglia which subserves the function of movement modulation. There likely exists a role of endogenous cannabinoids in the regulation of movement given its abundance in this area. The CB1 receptors are found in the striatum and caudate nucleus which are rich in GABA-ergic neurons, and pre-terminals of the internal and external globus pallidus, and substantia nigra. They are found in the glutamatergic pathways within the cortical systems and in the subthalamic nucleus (1).
The endocannabinoid system appears to inhibit glutamatergic pathways and increases GABAergic activity in the basal ganglia. It affects the dopaminergic pathway (2). It is speculated that the endocannabinoids may play a role in modulating the various neurotransmitter systems. While large clinical randomized controlled clinical trials may be lacking there is evidence that cannabinoids may reduce the clinical manifestations of motor tics (2).
Review of case studies and case series
There is a paucity of clinical trials studying the role of cannabis in movement disorders. Most of the data is from pre-clinical studies or case reports. Clinical research undoubtedly has been stunted given the scheduling of the agent under a schedule I category and other related factors.
In a small study of 12 patients, tetrahydrocannabinol was studied to determine effectiveness in treatment of tics(3). The Tourette Syndrome Symptom List (TSSL) was utilized for self-evaluations by patients. The examiners used the Yale Global Tic Severity List, Shapiro Tourette Syndrome Severity Scale for rating the severity of tics. A randomized controlled clinical trial was carried out. Those in the group where delta-9-tetrahydrocannabinol showed improvement compared to the placebo control group. There was great improvement using the TSSL with a p=0.15. Significant improvement found with complex motor tics using examiner ratings. Simple and vocal tics showed improvement (3).
In a case series of 19 patients, there were 60% who had much less motor tics after treatment with cannabinoids. There were 18 patients who felt they significantly improved (4).
The fact that the endocannabinoid system on which cannabinoids work is widely found within the basal ganglia which modulates fine movement correlates the function it has with modulation of movement.
While the scarcity of clinical trials is evident, cannabinoids continue to be used in clinical practice with some modicum of success for treatment of motor tics.
Koppel, B. Cannabis in the treatment of dystonia, dyskinesias, and tics. Neurotherapeutics. 2015, Oct. 12(4):788-792
Muller-Vahl, K.R., Kolbe, H., Schneider, U., Emrich, H.M. Cannabis in movement disorders. Forsch Komplementarmed. 1999. Oct. 6 Suppl 3:23-27.
Muller-Vahl, K.R., Schneider, U., Koblenz, A., Jobges, M., Kolbe, H., Daldrup, T., Emrich, H.M. Treatment of Touterret’s syndrome with delta 9-tetrahydrocannabinol (THC) a randomized crossover trial. Pharmacopsychiatry. 2002, Mar. 35(2):57-61
Abi-Jaoude, E., Chen, L., Cheung, P., Bhirkram, T., Sandor, P. J. Neuropsychiatry Clin Neurosci. 2017 29(4):391-400
Virginia Thornley, M.D., Board-certified Neurologist, Epileptologist
July 15, 2018
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
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.
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 phytocannabinoid. One needs 100 times the CBD to get the 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 the 2 are combined together, CBD will offset side effects of THC including paranoia, hyperactivity and agitation. This is a not known fact to those who self-medicate with pure THC. Because of this THC is medically recommended in conjunction with CBD. Smoking is illegal and not medically recommended as most people think. https://neurologybuzz.com/2018/04/02/medical-marijuana-vlog-series-part-i-mechanisms-medical-benefits-of-non-intoxicating-cannabidiol-and-tetrahydrocannabinol/
Pitfalls of self-medication
Sometimes patients self-medicate and smoke pure THC from dubious sources to alleviate symptoms, which is illegal and not medically recommended in Florida. However, the intoxicating effects 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. Self-medicating with THC from an unknown source is highly discouraged as there may be mold involved with the processing. 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 allowing better tolerance. THC is not recommended by itself because of side effects including paranoia, agitation and hyperactivity.
CBD by itself
With pure CBD, there are certain medical symptoms that are alleviated.
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, anecdotally. Everything else is 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.
CBD alone has no psychoactivity but medical value. CBD is combined with THC in order to offset its side effects of paranoia, agitation and hyperactivity.
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 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 undergoes registration which takes between 2-4 weeks. An e-mail 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 misentering of an e-mail causing a delay.
Regulated dispensaries in the Florida
In Florida, 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 the 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. A statement before the qualifying course on medical cannabis states that the physician can be questioned at any time by the FBI and authorities.
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.
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.
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. One must be mindful that there are different types of practices recommending medical cannabis. The best practices are those that are an already established practice which added medical marijuana to their repertory. Practices that are solely for medical marijuana may be of dubious quality. There are already horror stories of patients never getting a card after several months and phone calls not being advisef on what to do, being examined in a conference hall. As with any new innovative service, there will be legitimate practices and there will be those who meet the minimum requirement of care and service. http://www.tampabay.com/investigations/2018/05/04/floridas-medical-marijuana-program-is-attracting-troubled-doctors-its-like-the-wild-wild-west/
For doctors recommending, one must be well-versed in understanding 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 effects of the phytocannabinoids which is best 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 due diligence being up to date on legislations as well as the most recent research. The hard questions will come.
One must also follow the legal implications, current regulations which are frequently updated. It is the physician’s responsibility to understand the mechanisms, be current 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.
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/
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.
Virginia Thornley, M.D., Neurologist, Epileptologist
June 16, 2018
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.
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.
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).
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.
- 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
- Thomas, et al, “Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety,” Psychopharmacology, 2010, Jun., 204(2):361-373
- Casarotto, et al, “Cannabidiol inhibitory effect on marble-burying behavior:involvement of CB1 receptor,” Behav. Pharmacol, 2010, Jul., 21(4):353-358
Virginia Thornley, M.D., Neurologist, Epileptologist
May 22, 2018
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.
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).
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).
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).
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).
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).
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.
- 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)
- 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.
- 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)
- Rosenberg, et al, “Cannabinoids and epilepsy,” Neurotherapeutics, 2015, Oct., 12 (4):747-768.
- Devinsky, O., et al, “Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome,” New England Journal of Medicine, 2017, 376: 2011-2020.
- Devinsky, et al, “Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome,” NEJM, 2018, May, 378:1888-1897.
- Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open label interventional trial,” Lancet Neurology, 2016, Mar., 15 (3):270-8.
- Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
- 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.
Virginia Thornley, M.D., Neurologist, Epileptologist
May 6, 2018
There is a well-known correlation of use of cannabis whether it is medical or recreational to the onset of schizophrenia. It unclear if this could be to a direct correlation and disinhibition of the genetic component or the behavior of using it is a prodrome leading up to schizophrenia. This review seeks to elucidate the mechanisms in the correlation of the use of cannabis and onset of schizophrenia.
Mechanisms related to the underlying genetic composition
Schizophrenia may be linked when some of the normal pathways become disrupted with an introduction of THC. There are 4 genes that were described after a lifetime use of cannabis including KCNT2 which were THC responsive, NCAM1 and CADM2 are significant in functioning in post-synapse. With THC in the system, there are more post-synaptic density genes (1).
Mechanisms related to other neurotransmitter pathways influenced by cannabinoids
In one study, because of the alarming rate of potent synthetic cannabis used recreationally which was found to leave long-lasting schizophrenia disorder in recreational users, this has accelerated research into the pathophysiology. Because cannabinoids work on the CB1 receptor, it is likely that it plays a modulatory role on the other neurotransmitters that can give rise to schizophrenia including dopaminergic, glutamatergic and serotonergic pathways. These pathways are well-established as playing a role in a pro-psychotic state. High efficacy synthetic cannabinoids which are manufactured for recreational purposes are highly more potent compared to natural organic cannabinoids and there is an alarming increase in the correlation of schizophrenia in these users (2).
In one study it is thought to be due to the hypofunctioning of the glutamate system which is directly affected by THC. Exposure to tetrahydrocannabinol appears to reduce the activity at the level of the glutamate receptor as well as deregulate genes for synaptic function(1).
Susceptibility is related to the development of schizophrenia
In one animal model, the set-up tried to mimic a more real state seen where not all adolescents exposed to synthetic cannabinoids react by developing schizophrenia, there are some studies where all animals develop schizophrenia with exposure. In this animal model, they provided a model that resembles the human model more closely and found that exposure to synthetic cannabinoids in schizophrenia-prone animals caused hyperfunctioning of dopaminergic pathways compared to the control group who were not susceptible at the same dosages. There may be underlying genetic or environmental factors that cause certain individuals to become more prone (2).
THC can cause anxiety and behavioral disorders but can be prevented with CBD
In one animal study, it was found in a rat study that THC can induce anxiety and behavioral disorders. With THC administration object recognition was impaired in adolescent rates. The studies support effect on the developing brain in relation to cognitive impairment in the animal model. In addition, when rats were exposed to THC there was increased marble burying behavior which in scientific research is thought to signify anxiety or obsessive-compulsive type behavior usually ameliorated with serotonin reuptake inhibitors or benzodiazepines(4).
It was found, however, that a combination of CBD and THC or cannabidiol alone was administered, these behaviors were not produced or produced only minimally. The thought is that CBD is an allosteric competitive inhibitor at the CB1 receptor so that one sees less of the toxic undesirable effects of THC if administered alone (4).
Cannabinoids have a similar profile to atypical anti-psychotics and may be a possible adjunctive treatment in the treatment of psychotic events (5).
There is historical evidence that exposure to THC can give rise to schizophrenia in those individuals that are susceptible accounting for the fact that it does not happen to everybody exposed to it. This is related to its influence on serotonergic, dopaminergic and glutamate pathways. THC can induce anxiety, repetitive behaviors which are ameliorated by CBD. CBD may be a useful adjunctive treatment for psychotic disorders. However, the elucidated mechanisms are based on scientific research based on animal models which may not translate into humans.
- Guennewig, et al, “THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorder,” Transl. Psychiatry, 2018, Apr., 8(1):89.
- Fantegrossi, et al, “Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems, Drug Metab. Review, 2018, Jan, 50(1)
- Aguilar, et al, “Adolescent synthetic cannabinoid exposure produces enduring changes in dopamine neuron activity in the rodent model of schizophrenia,” Int. J. Neurpsychopharmacol., 2018, Apr., 31 (4):393-403.
- Murphy, et al, “Chronic adolescent delta9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive behavioral dysfunction which is prevented by concurrent cannabidiol treatment,” Cannabis Cannabinoid Res., 2017, 2(1):235-246.
- Deiana, et al, “Medical use of cannabis: a new light for schizophrenia?” Drug Test Analysis, 2013, Jan., (5)1:46-51
Virginia Thornley, M.D., Neurologist, Epileptologist
May 2, 2018
With the advent of a wide use of cannabinoids in neurological disease compared to previous times, attention hyperactivity deficit disorder has arisen as one of the possible disorders where patients may benefit. Because it starts in childhood, questions arise whether it may be applied to the pediatric patients with ADHD. If so, what are the long-term consequences on the developing brain?
Effect of cannabis in ADHD and on the brain
There is a paucity of literature on cannabis use in children with ADHD, most have been on adults. There are some recent clinical trials and its use in adult patients with ADHD. In a recent study on ADHD in adults, 30 patients were studied, 15 were in the placebo-controlled group and 15 were given Sativex oromucosal spray (combination CBD:THC). There was no statistical difference in cognitive performance although the score patterns on those on Sativex were higher. There was some improvement in attention. There was a significant improvement in emotional lability and hyperactivity (p=0.3). This implies that cannabinoids may play a role in adult ADHD (1).
In a study of 579 young adult patients with an early history of ADHD of which 129 had to be excluded, it was found that the dorsal attention network found in the parietal region was stronger in those with ADHD. The right fronto-parietal and right inferior frontal region connections were weaker in the ADHD group. The left prefrontal dorsal connections and the right prefrontal cortex connections in ADHD were reduced (2).
One of the key components of ADHD in children is motor dysregulation and weakened connections in the somatosensory region. The stronger connections in ADHD in the frontal-opercular regions suggests compensatory adaptations to maintain normal cognition. There are stronger right parietal region connections in patients with ADHD possibly suggesting maladaptive mechanisms. When patients with ADHD and cannabis use were studied it appeared that there were neuroadaptive processes. In those who used cannabis, there were stronger intrinsic connections with a superior delayed recall. There were stronger connections in the left fusiform gyrus that correlated with a) less cognitive interference, these are emotional thoughts or personality traits that can intrude and affect tasks at hand and b) better response inhibition performance, this is the ability to ignore distractions. This is consistent with other studies showing an increased task activation response (2).
Effect of cannabis on the fetus
Tetrahydrocannabinol is lipophilic and crosses the blood-brain barrier. It can get stored in the fatty stores which are likely the reason it may have a long-lasting effect. Cannabinoids have been found to cross the placenta and affect the fetus. It may result in hyperactivity and impulsivity in babies with cannabinoid exposure in utero (3). There was a greater incidence of inattention and delinquency in prenatal exposure to cannabis.
Effect of medical marijuana in early cerebral development
It was found that in adolescents who used cannabis, there is a reduction in the IQ by the age of 38. It was found that cannabinoid receptors influence axonal migrations as well as subcortical projections within the cerebrum. This affects synaptic connections during childhood and adolescence(4).
The adolescent brain is still not fully matured and likely still subject to neuronal plasticity and changes. It may be affected by substances. One study showed that the frontal lobe is vulnerable to cannabis in adolescents who used it heavily and that cannabis use may impact working memory (5).
During adolescence, when cannabis is initiated it may affect the neuronal circuitry developing in the immature brain. The richest regions in the brain with cannabinoid receptors are the prefrontal cortex, medial temporal lobes, striatum, white matter connections, and cerebellum. When cannabis is introduced during this neurocritically important time of development, these regions can become dysfunctional although some functional studies have shown altered, weakened, strengthened or combination of changes (2).
Some of the most common adverse effects
At high doses in chronic users, it was found to induce anxiety, panic attacks. It can increase blood pressure. However, clinically, it may control seizures
There is a paucity of literature on the effects of medical marijuana on the pediatric population. It has been mostly studied in adult patients. It is difficult to correlate the results of beneficial effects on adults on children since the pediatric brain is still developing. In adult patients with ADHD, apparently exposure to cannabis results in a superior delayed recall, there were fewer thought intrusions when completing tasks and better able to ignore distractions.
When exposed in utero, there was a greater risk of developing inattention, hyperactivity, and impulsivity in children who were exposed before conception. There was a greater tendency towards delinquency. In addition, adolescents who had been chronically exposed to cannabis may have had their working memory impacted. The adolescent period is significant from a neurological standpoint in brain development. There were mixed reports on connections being strengthened, weakened or a combination of the two being reported.
It is difficult to correlate the data of chronic medical cannabis exposure of adolescents in a patient who will use it for its medicinal value since the route, amount and administration and frequency will be completely and distinctly different. In addition, most of the adolescent data has been derived from those who had used it recreationally usually by smoking it heavily, there may be a synthetic component which may be detrimental and it is not clear what other substances may have been added.
In short, there is not enough scientific and clinical data to support the use of medical cannabis in pediatric patients. Most of the data is derived from animal studies or studies in adults where there are medical benefits. In the pediatric brain even while studies showed abnormal memory in chronic use it was studied in a very different population of heavy recreational users. Therefore, it is not clear if adult findings can translate into similar pediatric success and the same dysfunctional development of chronic heavy abusers would correlate with similar findings in pediatric patients using it for distinctly different reasons and dosing and administrations. If there is some adverse effect on the pediatric brain, it is unclear if the risks outweigh the benefits in a developing brain of the pediatric population. It may be used anecdotally in some practices with some benefits. Large clinical trials are needed to support this.
1. Cooper, et al, “Cannabinoid in attention-deficit/hyperactivity disorder: a randomized controlled trial,” Eur. Neuropsychopharmacol., 2017, Aug., 27 (8):795-808
2. Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.
3. Goldschimd, et al, “Effects of prenatal marijuana exposure on child behavior problems at age 10,” Neurotoxicol. Teratol., 2000, May-Jun., 22(3):325-326.
4. Scott, et al, “Medical marijuana: a review of the science and implications for developmental-behavioral pediatric practice,” J. Dev. Behav. Ped., 2016, Feb., 36 (2):115-123.
5. Jager, et al, “Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter fMRI study,” J. Am. Acad. Child Adolesc. Psychiatry, 2010, Jun., 49(6):561-572.