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References

Ramirez, B.G., Blazquez, C., del Pulgar, T.G., Guzman, M., de Ceballos, M.L. Prevention of Alzheimer’s disease pathologyby cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25:1904-13
Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G., Cuadrado, A., de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflam. 2012, 9:8
Lopez, A., Aparicio, N., Pazos, M.R., Grande, M.T., Barredo-Manso, M.A., Benito-Cuesta, I., Vazquez, C., Amores, M., Ruiz-Perez, G., Garcia-Garcia, E., Beatka, M., Tolon, R.M., Dittel, B.N., Hillard, C.J., Romero, J. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflam. 2018, May, 15:158

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

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

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.

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).

Skrabek, et al, “Nabilone for the treatment of pain in fibromyalgia,” J. Pain, 2008, Feb., (9)2:164:173
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

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.

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).

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.

Reference

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

synthetic cannabinoids

The fatal effects and mechanisms of synthetic cannabinoids including JWH compounds used recreationally

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 31, 2018

Introduction

Advocacy groups are well-versed and even the public is aware of the increasing popularity of medical marijuana use for medical purposes. Medical marijuana that is all organic all natural with no synthetic materials with high quality have the best-tolerated effects compared to synthetic products. However, with many research studies ongoing, there is the darker side of the equation from which the stigma first grew, its intent for recreation and subsequent abuse. Producers trying to evade the law have come up with far more potent and potentially deadly synthetic cannabinoids which escape detection through laboratory means.

There are spurts of news items regarding the increasing use of synthetic marijuana known as the street name “spice” or “K2.” It first became known in 2008 when the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) identified it as dangerous synthetic cannabinoids from herbal incenses with a remarkable affinity to the CB1 and CB2 receptors which were insidiously abused. These substances were left unchecked because they were initially difficult to identify through biomarkers or testing leading scientists to urgently study these compounds (3).

Typically, presentations occur in groups of patients in the emergency room arising from a single source of distribution at a time. There can be a variety of symptoms because of admixed substances. They have arisen in popularity because they may not be detected by conventional drug testing. Synthetic cannabinoids produce more intense psychoactive effects and by the same token more intense side effects. In animal models, synthetic cannabinoids are 2-100 times more potent than tetrahydrocannabinol in terms of analgesic, anti-inflammatory, anti-seizure effects. It is also thought to be more potent for anti-cancer growth. Because of this, while the beneficial effects are more prominent, by the same token, medical and psychoactive emergencies may result due to its more intense effects through the endocannabinoid pathway. With the added effect of excessive use, this only magnifies the potentiation of effects.

This is likely also the reason why synthetic cannabinoids used medically may provide more benefit, but by the same token are less tolerated and more side effects are noted.

JWH-018 or K2 or Spice and mechanisms

The synthetic cannabinoid “K2” or “Spice” is also known as JWH-018. Dangerous effects of K2 and other synthetic cannabinoids, because they work through the CB1 and CB2 receptors, are potentiations of the usually mild effects of phytocannabinoids from the Cannabis sativa plant. This can lead to changes in the levels of dopaminergic, serotonergic and GABAergic neurotransmitters in the system causing symptoms. There is a high affinity of synthetic cannabinoids to the CB1 receptor through which psychoactive properties of cannabinoids are manifest. It produces similar effects to delta-9-tetrahydrocannabinol which is the psychoactive metabolite from the Cannabis sativa plant but is much more potent. Synthetic cannabinoid metabolites may still remain active and exerts long-lasting effects in addition to the effects of the parent compound. The CB1 receptor is predominantly found in the nervous system while the CB2 receptor is found mostly in the immune system and in other organs to a lesser extent. Synthetic cannabinoids interact with the CB1 receptor pre-synaptically which is a G-coupled protein. Synthetic cannabinoid agonists interact with the CB1 receptor and modulate voltage-gated channels that inhibit sodium, potassium and N-sodium channels and P/Q-type sodium channels thereby reducing the membrane potentials (5).

Synthetic cannabinoids were originally manufactured as a therapeutic agent to exert effects on the cannabinoid receptor.

It is extensively metabolized by cytochrome p450 and activates the cannabinoid receptors (CBR). The most significant cytochrome is CYP2C9 (1) which is found predominantly in the gastrointestinal tract and liver. CYP2C9*1 is the wild type while CYP2C9*2 and CYP2C9*3 are the more common variants. It was found that CYP2C9 *2 tended to metabolize JWH-018 3.6 times more than CYP29C*1 which is likely why there is variation in toxic effects among different individuals when abused (1). Genetic polymorphisms may lead to potentiation of the effects. Other synthetic cannabinoids include JWH-073, CP-47 and 497 (3).

6 other synthetic cannabinoids that have been identified

Six synthetic cannabinoids were characterized from illicit drugs including MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA. The toxic effects include cardiotoxicity, seizures and renal damage (2). These have greater effects compared to those of THC. The study shows that synthetic cannabinoids are being manufactured and used as substitutes for THC with greater effects and potentiation (2).

There are hundreds of other synthetic cannabinoids that have been identified.

Dangerous side effects of synthetic cannabinoids

Synthetic cannabinoids affect the gastrointestinal and neuropsychiatric systems and additionally can cause cardiogenic effects. Adverse effects include tachycardia, chest pain, myocardial ischemia, hypertension, confusion, agitation, hallucination, seizures, cerebrovascular vasoconstriction, stroke, and nausea. There have been other reports involving arrhythmias, psychosis, memory loss, cognitive impairment and even fatality (5).

In one study of 141 patients, there were atypical symptoms of psychomotor retardation, hypotension, bradycardia. 75% of blood samples had possibly XLR-11. 24 urine sample came back positive for synthetic cannabinoids, 74% had XLR-11, while 35% had carboxamide indazole derivatives. There were no JWH compounds, opioids, sedative-hypnotics, or imidazoline receptor agonists detected. It is not clear if there may be other undetectable psychotropic agents that may have been mixed causing the unusual symptoms not typical for cannabinoids. In addition, these were patients that came from a nearby psychiatric facility where potentially other neuropsychotropic agents may have interacted (4).

In summary

Clinicians should recognize the clinical symptoms from synthetic cannabinoids and possible adverse side effects as it is emerging as one of the popular drugs of abuse. Once it was discovered there was a ban on synthetic cannabinoids decreasing the wide usage but there has since been a resurgence. They potentiate their pharmacologic effects at the CB1 receptor 2-100 times that of tetrahydrocannabinol but by the same token may cause medical and psychiatric emergencies.

References

Patton, et al, “Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome p4502C9 and variants,” Biochem. Biophys. Res. Commun., 2018, Apr., 6, 498 (3):597-602.
Gamage, et al, “Molecular and behavioral pharmacological characterization of abused synthetic cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA,” J. Pharmacol. Exp. Ther., 2018, May, 365(2):437-446.
Brents, et al, “The K2/spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products.” Drug Metab. Rev., 2014, Feb., 46(1):72-85.
Sud, et al, “Retrospective chart review of synthetic cannabinoid intoxication with toxicologic analysis,” West J. Emerg. Med., 2018, May, 19(3):567-572. doi: 10.5811/westjem.2017.12.36968
Castaneto, et al, “Synthetic cannabinoids: epidemiology, pharmacodynamics and clinical implications,” Drug Alcohol Depend., 2014, Nov., 1:12-41

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).

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).

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.

References:

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.

autism

Part XIV Medical marijuana: effects on autism and developing brain in pediatric patients

autism

Medical marijuana: effects on pediatric patients with autism and the developing brain

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

Medical cannabis is being more and more commonly used in medical conditions specifically neurological. The CB1 receptor is found predominantly within the nervous system and in a few other organs on a lesser basis. The CB2 receptor is mainly in the immune system and found in other organs to a lesser extent.

Recent arguments have arisen promoting medical cannabis in children particularly in those with autism and attention deficit hyperactivity disorder. It has already been well-established in patients with epilepsy. However, the effects on the developing brains of children have not yet been well-documented as it is not yet widely used or studied in the pediatric population. There are many animal models but this does not always correspond to translate into similar human findings.

Effect in autism in animal models and clinical studies

A current topic of debate is not only using THC in pediatric patients but those with autism. Autism is part of the pervasive developmental disorder consisting of social inhibition and isolation including poor eye contact, delayed language skills, aggressive behavior and may be characterized as having stereotypies such as flapping of the arms. Self-injury, eating and sleep disorders may occur. The etiology may be related to genetic, neurobiochemical or environmental and the exact cause is unclear.

In one animal model study, mice with induced Dravet syndrome-like symptoms was noted to improve in autistic-like social interactions with the addition of low dose cannabidiol (2) of 10mg/kg. At low doses, the DS mice interacted more with stranger mice. At higher doses, this was not noted. Dravet syndrome is a type of epileptic syndrome affecting the SCN1A gene causing medically refractory seizures combined with autism. However, this was an animal model. Scientific studies do not necessarily translate into positive human clinical results.

There was one case report of a six-year-old boy with early autism. Dronabinol (delta-9-THC) was administered at 3.62mg a day and followed for 6 months. Using the ABC scale (aberrant behavior checklist), the patient improved in terms of stereotypies which were less, lethargy was reduced, hyperactivity improved, and inappropriate speech improved (4).

Endocannabinoid system and mechanisms in relation to autism

There are several lines of thinking regarding the role of the endocannabinoid and autism. It is thought that the endocannabinoid system plays a role in neurological development, but can also be modulated by outside cannabinoids. Another line of thinking is that autism spectrum disorders may be related to disrupted pathways that have been affected by the endocannabinoid pathway (5). In one animal study, it was found that the oxytocin peptide may be responsible for disrupting normal signaling pathways giving rise to autism spectrum disorders. Oxytocin appears to be crucial in mediating social reward which is impaired in autistic patients. Anandamide seems to play a role in the signaling pathways for oxytocin which is responsible for the social reward. Social reward is aberrant in those with autism and this pathway thought to play a key role in causing its pathogenesis. By increasing anandamide at the CB1 receptor, ASD and social impairment is improved (5).

Effect on a 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.

Effect on 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(3).

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. (1)

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 (6).

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

In summary

There is a small body of evidence from a scientific standpoint that cannabis may work to help alleviate autism-like symptoms based on the animal models. There is a not enough evidence from a clinical evidence standpoint in human studies to support its use in pediatric patients, with one case report that it helped with impulsivity, reduced lethargy, and inattention. Randomized placebo-controlled clinical trials are needed.

Research has found that cannabinoids may help oxytocin and disrupted signaling pathways that play a role in social reward which is impaired in autism. At present, there is evidence that cannabis may affect neurocognitive development but these are studies in pregnant mothers who used it heavily recreationally and adolescents who used it heavily. It is unclear if there may be a similar impact when used in the pediatric population at a medical dosage and administration as there are not enough studies to expound on this.

Reference

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.
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.. 114 (42):11229-11234.
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.
Kurz, et al, “Use of dronabinol (delta-9-THC) in autism: a prospective single-case study with early infantile autistic child,” Cannabinoids, 2010, 5 (4):4-6.
Wei, et al, “Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment,” Cannabis Cannabinoid Research, 2016, 1(1):81-89
Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.

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.

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.

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.