Tag Archives: CB2

Tourette's Syndrome

Medical cannabis in Tourette’s syndrome: case reports and a small randomized controlled clinical trial

Virginia Thornley, M.D., Neurologist, Epileptologist
June 11, 2018

@VThornleyMD

Introduction
When one hears Tourette’s syndrome the glorified Hollywood impression young person who shouts obscenities comes to mind. It is composed of complex motor or vocal tics generally preceded by a premonitory urge. Vocal tics may consist of coprolalia and echolalia. Motor tics may involve complex actions including copropraxia or simple motor tics. Obsessive compulsive disorder and other neuropsychiatric conditions are often associated with it.

The underlying problem is thought to be related to an imbalance of the neurotransmitters necessary to maintain the fine coordination necessary to avoid excessive motor activity. When that balance is impaired there is less inhibition of motor loop control resulting in reverberating loops and excess movements involving motor groups including muscles controlling speech and body movements. Because the pathophysiology is not entirely clear, these may be some of the most challenging neurological disorders in terms of treatments from a neurological standpoint.

Background on Cannabinoid Mechanisms
With the advent of medical cannabis used in neurological conditions, new indications are discovered. The mechanism is at the level of the endocannabinoid system already inherent within the system. There are 2 receptors, CB1 and CB2. The CB1 receptor is found mostly within the nervous system. The CB2 receptor is mostly in the immune system but is found in other organ systems to a lesser extent. Tetrahydrocannabinol (THC) is a mimetic of Anandamide which works within the endocannabinoid system and has medical properties. THC interacts with the CB1 receptor which is responsible for psychoactive properties most people are familiar with. It is likely at the CB1 receptor where other neurological symptoms are alleviated since this most abundantly found in the nervous system and many neurological symptoms are ameliorated with medical cannabis. Cannabidiol (CBD), which is non-psychoactive, is a pharmacomimetic of 2-AG or diarachidonylglycerol. It is an non-competitive allosteric modulator of the CB1 receptor which alleviates any side effects from THC when they are combined together (1).

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Clinical Reports
There is one report of a patient treated with nabiximol where there was improvement of tics. There was overall improvement in quality of life and global improvement. There was lessening of premonitory urges. Patients feel the premonitory symptoms are more bothersome. In one study anti-psychotics helped ameliorate the motor tics but did not improve the premonitory symptoms (2). Nabiximol was used in this study where 1 puff contained 2.7mg of THC and 2.5mg of CBD. Assessments included the Yale Global Tic Severity Scale (YGTSS), Tourette’s Syndrome Symptom LIst (TSSL), Modified Rush Video Tic Scale, Premonitory Urge for Tic Scale, Global Clinical Impairment, Visual Analogue Scale for satisfaction for the GTS-Quality of Life. The study showed the best results in the quality of life in terms of alleviating premonitory urges. Larger clinical trials are needed to further this study (2).

In a recent case report, THC (trademark Sativex) was used with success to treat a patient using 10.8mg THC and 10mg CBD daily. Yale Global Tic Severity Scale (YGTSS) and the Original Rush Video Tic Scale were used as measures of evaluation. The results demonstrated effective use of THC in combination with THC for treatment in medically refractory patients (5).

In one single dose, cross over study in 12 patients and a randomized trial in 24 patients spanning 6 weeks was performed (3). The study demonstrated that THC reduces tics without any disruption in cognitive function. Neuropsychological impairment was not seen (3).

In the randomized double blinded placebo-controlled clinical trial of 24 patients, THC of up to 10mg was used in the treated cohort over 6 weeks. Measures used included the Tourette’s Syndrome Clinical Global Impression Scale (TS-CGI), Shapiro Tourette Syndrome Severity Scale (STSS), the Yale Global Tic Severity Scale (YGTSS), Tourette Syndrome Symptom List (TSSL) and the videotape based rating scale. Patients were rated at visits 1 for baseline, visits 3-4 during treatment and visits 5-6 after withdrawal. There was a significant difference between both groups. There was a significant reduction in motor tics, vocal tics and obsessive compulsive disorder. No significant adverse cognitive effects were noted (4).

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More randomized controlled clinical studies are necessary
While there may be a paucity of large clinical trials of the use of medical cannabis in Tourette’s syndrome, tetrahydrocannabinol is a potential therapeutic agent in a neurological disorder where treatment options are very limited and often times unsuccessful. Adverse side effects can preclude treatment using conventional pharmaceutic agents.

While large randomized controlled clinical trials are necessary in providing standard of care, tetrahydrocannabinol has emerged as a potential treatment option used by clinicians who are on the frontlines of treating this debilitating disorder.

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Reference
1. Laprairie, et al, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” Br. J. Pharmacology, 2015, Oct., 172(20):4790-4805
2. Kanaan, et al, “Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximol,: Brain Science, 2017, Apr., 7 (5):47
3. Muller-Vahl,”Cannabinoids reduce symptoms of Tourette’s syndrome,” Expert Opin Pharmacother., 2003, Oct., 4(10):17-1725
4. Muller-Vahl, “Delta-9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6 week randomized trial,” J. Clin Psychiatry, 2003, Apr., 64 (4):459-65
5. Trainor, “Severe motor and vocal tics controlled with Sativex®,” Australas Psychiatry, 2016, Dec, 24 (6):541-544

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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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medical marijuana

A review of mechanisms in medical marijuana: the endocannabinoid pathway, receptors, tetrahydrocannabinol, and cannabidiol 

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

April 28, 2018

Introduction

The Cannabis sativa plant has been known since the beginning of time. It can be traced back 5000 years ago when it was first known to man to alleviate common complaints. It came into the American pharmacopeia in the 19th century then abolished in the 1930’s, likely not coincidentally as the era of prohibition was lifted. It is known to treat ailments such as chronic pain and migraine. In the middle ages, it was used to treat headaches, vomiting, diarrhea, bacterial infections and pain from rheumatological conditions. It was previously known for its psychoactive properties.  It is recently making a resurgence in popularity regarding its medical value. The issue is a topic of hot debate as state laws are at odds with federal laws. Currently, as of April 2018, it is still recognized as a category 1 drug, meaning it is not officially proclaimed to have any medical value despite the long rich history of treating medical symptoms. It is lumped in with other drugs of abuse such as heroin and cocaine.

Background on the Cannabis sativa plant and their metabolites

The Cannabis sativa plant is abundantly rich in phytocannabinoids, the most commonly known and used for its therapeutic value are cannabidiol and tetrahydrocannabinol. The endocannabinoid pathway is comprised of receptors that are coupled with G proteins and cannabinoids (1). In the Cannabis sativa plant, there are 80 phytocannabinoids that can bind to a cannabinoid receptor.

There are 8 major cannabinoids including cannabigerolic acid, delta-9-tetrahydrocannabolinic acid A, cannabidiolic acid A, delta-9-tetrahydrocannabinol, cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabivarin in the different strains of Cannabis sativa (1).

Ehlsoly, et al, classified it into 11 categories: cannabigerol, cannabichromene, cannabidiol, ∆9-trans-tetrahydrocannabinol, ∆8-trans-tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabitriol, and miscellaneous. ∆9 -trans-tetrahydrocannabinol , cannabinol, and cannabidiol are the most well-studied and well-known.

Cannabidiol is extracted from the hemp portion of the plant considered a male part of the plant, there are no psychoactive properties in cannabidiol. Psychoactivity is defined as anything above 0.3% of THC. Tetrahydrocannabinol is derived from the female portion of the plant, particularly the flowers. Conditions are such that in nurseries only a certain amount of sunlight is given to the plants so that specific strains can be grown. Some plants will be richer in cannabidiol, others will be more THC pure and other swill have an equal amount of CBD and THC but it depends on how the plants are grown and under what conditions.

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Endocannabinoid pathway

It is through the endocannabinoid pathway that one gets the sense of well being after exercise or eating chocolate. It is not through endorphins, serotonin or noradrenergic neurotransmitters as they are too large to cross the blood-brain barrier. Tetrahydrocannabinol acts as a mimetic of Anandamide while cannabidiol acts as a mimetic of 2-Arachidinoylglyerol (or 2-AG). The endocannabinoid system works through cannabinoids, the receptors, transporters, and enzymes.

Receptors

The phytocannabinoids work on cannabinoid receptors. The endocannabinoid system is mediated by 3 parts: the cannabinoids, the cannabinoid receptors, and the enzymes. The receptors are of 2 types, CB1 which is found primarily in the nervous system especially in the areas that subserve pain modulation, memory and movement. The CB2 receptor is more peripherally found specifically in the immune system. The CB2 receptor is found to a lesser extent in other organs including tissues of reproduction, pituitary, heart, lungs, adrenal and gastrointestinal systems.  Cannabinoids also react with the TRPV receptor or the transient receptor cation channel subfamily V. They can also act on G receptors including GPR55 thought to be significant in controlling seizures. Other receptors include GPR12, GPR18, and GPR119 (2).

Tetrahydrocannabinol and cannabidiol and their effect on receptors

THC and CBD are the most well-known and well-studied. THC has psychoactive properties and works as a partial agonist on the CB1 receptor and the CB2 receptor. Cannabidiol which has no psychoactive properties works as an antagonist on CB1/CB2 receptor and an agonist on the CB1 and CB2 receptor. Rather than decreasing the effects of THC, it works in a synergistic manner in combination with THC. It potentiates the THC effects by increasing the CB1 densities. CBD increases vanilloid pain receptors, reduces metabolism and reduces re-uptake of anandamide, THC’s mimetic component. Other studies suggest CBD acts as an indirect agonist by interacting with the CB1 receptor so there are less psychoactive symptoms from THC when the two are combined.

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Pharmacokinetics of tetrahydrocannabinol

Regardless of the way of taking it, the protein binding and the and volume of distribution are not affected by the route of taking it. Pharmacokinetics of creams and vaporizers are unclear. Smoking THC appears to exert an effect within minutes of intake and bioavailability is variable depending upon the extent of inhalation ranging between 2-69%. The effect is within minutes. Half-life increases with each inhalation at 2 puffs inhaled for THC it is 1.9 hours and 5.3 hours in CBD at 8 inhalations it is 5.2 hours in THC and 9.4 hours in CBD at a dosage of 5.4mgTHC/5.0mg CBD and 21.5mg THC/20 mg CBD respectively.

Oral routes may seem to be safer but have more adverse effects including GI symptoms such as nausea, vomiting, and diarrhea. Oral mucosal absorption is rapid within 15 minutes to 60 minutes. Oral tablets are lower in the rate of absorption at about 0.6 to 2.5 hours. The rate of elimination, when taken orally, is biphasic, initially occurring at 4 hours then 24-38 hours after ingestion.

In summary

There is much research ongoing on the mechanisms underlying the medical value of medical marijuana. It is now thought that cannabigerolic acid may have medicinal properties as well. So far, the most well-known and well studied are delta-9-tetrahydrocannabinol and cannabidiol. Most likely as research continues, greater value will likely be attributed towards the phytocannabinoids.

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Introduction/Disclaimer

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References

  1. Wang, et al, “Quantitative Determination of delta 9-tetrahydrocannabinol, CBG, CBD, their acid precursors and five other neutral cannabinoids by UHPLC-UV-MS,” Planta. Med, 2019, mar., 84 (4):260-266.
  2.  Landa, et al, “Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice,”Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2018, Mar; 162(1):18-25.
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Epilepsy, pain

Cannabidiol: Is there any scientific evidence? Review of some of the novel mechanisms of action in analgesic, anti-epileptic, anti-inflammatory, anti-tumorigenic and anxiolytic effects 

Virginia Thornley, M.D., General Neurologist and Epileptologist

@VThornleyMD

February 16, 2018

Introduction

Cannabidiol (CBD) is the little known medical component without the euphoria used for medical indications such as analgesic, anti-inflammatory, anti-epileptic and anxiolytic effects. In the pathway for endocannabinoids, cannabinoid exerts its therapeutic effects by binding to the CBD1 receptor found in the brains and the nerves exerting their analgesic effects. CBD does not have the same euphoriant effect as THC its counterpart which is better known to the public with much stigma. CBD will need to be 100 times more potent to have the same euphoria as THC making it relatively safe to give without the intoxicating effects. THC or delta-tetrahydrocannabidiol is the main psychoactive component in the marijuana plant, the one finds in the street drugs which has caused such a stigma shadowing the beneficial effects of the plant. Cannabidiol is also thought to work on the 5HT1 receptor giving its anxiolytic properties. This review seeks to understand some of the laboratory research that study the underlying mechanisms for its beneficial actions.

Cannabidiol works on CBD1 receptor and is thought to have an analgesic and anti-inflammatory role in diseases. In many states, it still outlawed to have in possession but growing clinical evidence shows that it can be used in pain syndromes. In the state of Florida there are 10 conditions recognized that can be treated with CBD. It is most commonly used in pain from stage IV metastatic cancer. Cannabidiol has been found to have anti-inflammatory, anti-tumorigenic, analgesic, anti-epileptic and anxiolytic properties.

Analgesic effects

CB1 receptors are found to be expressed in anterior horn cells. The CB2 receptors possibly reduce pain by acting on the neutrophil accumulation and mast cell degranulation which can reduce pain both of these processes increase inflammatory algesia(1).Analgesia has been demonstrated with cannabinoids in visceral inflammation and pain due to peripheral neuropathies, important areas of therapeutic considerations.

Anti-seizure effects

Some of the vast scientific research for cannabinoid is found in the animal models for epilepsy. Cannabinoids exert effects on CB1 and CB2 receptors in the hippocampus where it has a weak affinity(5). CBD1 receptors affect transmission in the synapses through the voltage-gated calcium and potassium channels. There are studies on the effects of CBD in refractory types of epilepsy such as Dravet’s syndrome one of the SCN1a genetic disorders affecting the sodium channel manifesting as severe myoclonic epilepsy. Mechanisms of CBD include increasing excitation of the inhibitory effect of the hippocampus where seizures are propagated.  At low doses, it helps with autism and impaired cognition.  It may exert its effect by working against GPR55(7), TRPV1 in addition to voltage-gated voltage-gated potassium and sodium channels. Another study supports the role that cannabinoids may play in shifting the inhibition of glutamatergic effects and GABAergic effects in the hippocampus mediated by CB1 receptors. In the rat model, it was suggested that seizures can upset the balance of these glutamate and GABA systems (4). 15 minutes after an induced seizure, there is increased 2-arachidonylycerol which is a CB1 agonist suggesting cannabinoids act as a negative feedback loop for seizures(4). In addition, it was found there are more CB1 receptors in the hippocampi with induced seizures compared to control suggesting plasticity of the brain with a compensatory increase in CB1 receptors in response to increased seizures(4). CB2 receptors are related to the immune system and are limited in the CNS. Cannabinoids affect calcium homeostasis and may provide its neuroprotective effects. Growing evidence shows case series, case reports and anecdotal reports on patients having fewer seizures on cannabidiol. Large case-controlled clinical randomized trials are needed.

Anti-tumor effects

There appears to be increased cancel cell death, reduced viability and reduced numbers of metastatic cells. In one study, it is found to reduce epidermal growth factor-induced multiplication and chemotaxis of cells in breast cancer. In mouse models, it inhibits macrophage recruitment in tumor-related cells.n It can potentially inhibit metastasis and proliferation and may provide a novel therapeutic option in breast cancer(2).

Anxiolytic effects

It works on the 5HT1 receptor by altering effects on this receptor the exact mechanism is unknown accounting for anxiolytic properties(6).

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Anti-psychotic effects

CBD may alter the effects of THC and reduce its psychoactive properties (6).

 

Alternative treatment in opioid use

CBD might also work in place of opioids with the growing epidemic of chronic pain and overuse of opioids, CBD may be an alternative analgesic for chronic pain without the effect of tolerance or sedating properties. CBD was found to reduce the reward effects of morphine and does not have the same properties of tolerance. CBD does not have the same euphoria and THC and works on pain(6).

In summary, it is an exciting time for research in the use of cannabinoids. There are innumerable basic science research studies demonstrating the therapeutic effects at the cellular level. Large randomized clinical trials are still needed to gain information in using cannabinoids in humans.

Introduction/Disclaimer

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https://neurologybuzz.com/

References

1. Rice, AS, et al, “Endocannabinoids and pain: peripheral and spinal analgesia in inflammation and neuropathy, ” Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002, Feb., 66(2-3)246-256.

2. Elbaz, E. et al, ” Modulation of tumor microenvironment and inhibition of EGF/EGFR pathway: novel mechanisms of Cannabidiol on breast cancer,”Molecular Oncology, 2015, Apr., 9(4):906-919.

3. Welty, W.E., et al, “Cannabinoids: the promises and pitfalls,” Epilepsy Currents, 2014, Sep.-Oct., 14(5):250-252.

4. Wallace, MJ, et al, ” The endogenous Cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy, ” The Journal of Pharmacology and Experimental Therapeutics, 2003, Oct., 307(1):129-137.

5. Gaston, T. et. al, “Pharmacology of cannabinoids in the treatment of epilepsy, ” Epilepsy Behavior, 2017, May, 70:313-318.

6. Volkow, Nora, “The biology and potential therapeutic effects of cannabidiol,” National Institute on Drug Abuse Senate Caucus on International Narcotics Control, 2015, June.

7. Kaplan, et.al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome, “Proceedings of the National Academy of Science, 2017, Oct.

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