Cancer research and cannabinoids

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

Virginia Thornley, M.D., Neurologist, Epileptologist

June 24, 2018

@VThornleyMD

https://neurologybuzz.com/

Introduction

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

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

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

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Endocannabinoid system

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

Endocannabinoids and the role in cancer

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

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

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

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

Effect on tumor cells

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

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

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

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

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

In summary

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

References

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

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

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

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

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

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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.

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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.

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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.

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References

  1. 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.
  2. 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.
  3. 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.
  4. 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
  5. Castaneto, et al, “Synthetic cannabinoids: epidemiology, pharmacodynamics and clinical implications,” Drug Alcohol Depend., 2014, Nov., 1:12-41

 

 

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medical marijuana

Cannabinoids and effects on other organ systems: cardiomyocytes and the gastrointestinal system

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 8, 2018

Introduction

Cannabinoids are being more and more widely used in a variety of neurological conditions. This always leads to the questions of side effects and will it interacts with other medications? Because this is wholly unchartered territory,  in order to answer these questions, it is necessary to understand the underlying mechanisms.

Cannabinoids can cause tachycardia

Phytocannabinoids, when ingested, can induce tachycardia. The metabolism of cannabinoids by cardiomyocytes likely impacts the side effects elicited in cardiac cells. CYP2J2 is the most significant cytochrome p450 which metabolizes endocannabinoid anandamide (AE) into the cardioprotective epoxides. 6 phytocannabinoids were studied in one paper including delta-9-tetrahydrocannabinol, cannabinol, cannabidiol, cannabigerol, and cannabichromene. These were found to be metabolized more quickly compared to anandamide. The cannabinoids may potentially inhibit the metabolism of anandamide by CYPJ2 such that its effects are still circulating in the system. The most significant inhibition was from delta-9-tetrahydrocannabinol. It follows a non-competitive inhibition model such that the cardioprotective epoxides are not formed as abundantly as they should by the cytochrome p450 CYP2J2 (1).

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The cytochrome P450 system has a significant impact on the metabolism of cannabinoids. Tetrahydrocannabinol is metabolized by CYP2C19 and CYP3A4. cannabinol is metabolized by CYP2C9 and CYP3A4. Synthetic cannabinoids include JWH-018 which is metabolized by CYP1A2 and CYP2C9 and AMC2201 which is metabolized by CYP1A2 and CYP2C9.

The cytochrome P450 enzymes are also thought to be involved in the metabolism of tetrahydrocannabinol. CYP2C9 greatly influences the metabolism of tetrahydrocannabinol. Cytochrome P450 3A4 is important in the metabolism of THC and CBD (2).

Cannabinoids in relation to hyperemesis syndrome

Once abdominal pain has been explored regarding medical etiologies, and there is a presence of 1-year history of cannabis use usually weekly, this diagnosis comes to mind. It usually involves cyclical vomiting associated with nausea. The mechanism is thought to be related to dysregulation by the endocannabinoid pathway in relation to the gastrointestinal tract. The CB1 receptor by which THC or tetrahydrocannabinol exerts it actions is also present in the GI tract. Exogenous cannabinoids may dysregulate the normal endocannabinoid pathway thereby affecting the GI tract through the down-regulation of the normal CB1 receptors so that it is no longer sensitive to endocannabinoids which regulate the system. This results in a dysfunction of the GI tract clinically manifested as cyclical nausea and vomiting. A disruption of the cannabinoid receptors may occur resulting in slowed motility of the gut. Relief can occur with use of hot water which influences the TRPV receptor a G-related coupled protein

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Introduction/Disclaimer

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References

  1. Arnold, et al, “Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2,” J. Inorganic. Biochem., 2018, Apr., 7(184):88-99 doi: 10.1016/j.jinorgbio.2018.03.016. (Epub ahead of print)
  2. Stout, et al, “Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review,” Drug Metab. Rev., 2014, Feb., 46(10:86-95.
  3. Lapoint, et al, “Cannabinoid hyperemesis syndrome: public health implications and a novel model treatment guideline,” West J Emerg Med, 2018, Mar., 19(2):380-386.

 

 

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schizophrenia

Cannabidiol may treat psychosis while tetrahydrocannabinol can induce schizophrenia in those susceptible  

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

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).

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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).

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In summary

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.

About

Introduction/Disclaimer

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References

  1. Guennewig, et al, “THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorder,” Transl. Psychiatry, 2018, Apr., 8(1):89.
  2. Fantegrossi, et al, “Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems, Drug Metab. Review, 2018, Jan, 50(1)
  3. 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.
  4. 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.
  5. Deiana, et al, “Medical use of cannabis: a new light for schizophrenia?” Drug Test Analysis, 2013, Jan., (5)1:46-51
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