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Medical

Christine Yoshioka, NP Objectives

Brief in cultures

Review of the Endocanabinoid system

Exogenous cannabis

Medical research involving cannabis and federal restrictions History of Cannabis

Highly valued and used by many cultures throughout history

3000 years ago anxiety relief with (ingested cannabis) in ancient India

Found in 2500 year old tombs in Eastern China

Cannabis in America

1816 King James I ordered colonies to grow for rope and paper products

1850 medicinal preparation became available in the US

1906 Pure Drug and Food Act - required certain drugs including cannabis to be accurately labeled and the states began to restrict the sale

1937 The Tax Act was passed which made it illegal to possess or transfer cannabis

1970 The Supreme Court determined the Marijuana Tax Act was unconstitutional, and at the same time the Controlled Substance Act was passed labeling Marijuana as a Schedule I. Cannabis

Cannabis possesses over 100 different that modulate analgesia and anti-inflammatory pathways and provide neuroprotection, among other functions.

In 1960 THC was identified as the primary bioactive component of cannabis

2AG and AEA were identified 25 years later.

Also found that the body could produce naturally occurring substances, called endocannabinoids (ECS) which could mimic THC activity (ECS) basic review

ECS is comprised of endocannabinoids, their receptors, and the associated mediating for synthesis and degradation ECS basic review

There are 5 known EC produced by the body

(AEA), 2-archidonoylglyceral (2AG), 2-archidonoylglyceral ether (noladin ether), O- archidonoyl ethanol amine (), N- arachidonoyl

AEA and 2AG are the most studied and recognized ECBs are normal at low levels when the body is in homeostasis. They begin to be synthesized in large quantities when stimulated as a response to painful stimuli, bacterial and/or viral infection, stress response, or inflammation.

The primary purpose of the ECS is to provide homeostasis for many metabolic functions, such as , inflammation, and energy modulation.

Cannabinoid Receptors

Cannabinoid receptors are G-protein coupled receptors that are activated by 3 major groups of ligands.

Endocannabinoids produced by the body, cannabinoids produced from the cannabis plant, and

2 principal subtypes of cannabinoid receptors are CB1Rs and CB2Rs Which receptors are more prevalent the CNS?

CB1Rs CB2Rs Endocannabinoid Ligands

Produced on demand Acts locally Binds to transmembrane G protein receptors, principally inhibiting neurotransmitter release

Cannabinoid 1 2 CB1R CB2R (brain spinal cord, (immune cells) PNS, organs, tissues) CB1Rs

CBR1s reside heavily within the CNS and are known for the neurologic affects when activated.

It acts presynaptically and inhibits the release of , L- glutamate, GABA, NE, DA, and 5 hydrotryptamine.

They also have receptors within the digestive organs, including pancreas, liver, small intestines, and large intestines, muscle fibers and adipocyte cells.

CB1Rs

CB1Rs found lining the hippocampus and limbic system help regulate emotions.

Blissful euphora.

Modulate anxiety and depression.

Augmentation of eCB signaling has been found to decrease depression and anxiety symptoms.

If CB1Rs are blocked increased symptoms will occur.

CB1Rs are also located in the basal ganglia and hypothalamus which regulate appetite and gastric motility

This led to the development of which drug used to treat cancer-related anorexia and nausea symptoms? CB2Rs

CB2Rs are found peripherally in the immune system tissues. They have almost no psychoactive affects and are found along the spinal column or bone marrow, very few receptors in the brain.

CB2Rs are predominant in leukocytes and appear to be the key mediators of cannabinoid regulation of the immune and inflammatory systems.

When blocked there is inhibition of splenocyte production and in-vivo cell-death.

When macrophage CB2Rs are stimulated they inhibit proliferation and the release of pro-inflammatory factors, and decrease phagocytosis. Currently 25 states have passed laws permitting limited use of medicinal cannabis for specific medical conditions.

Which of these states has NOT done so?

Nevada

Wisconsin

Arkansas

Louisiana

Medical Cannabis Research

Research is severely limited in humans due to Schedule I listing under federal law

Since the 1960s the federal government has only approved the University Mississippi’s School of pharmacy to grow cannabis.

In July 19, 2016 the DEA was petitioned to change Cannabis to a Schedule II drug but cited no currently accepted medical use in patient treatment. Current Research

Epilepsy, HIV neuropathy, chemotherapy-induced nausea, anorexia, multiple sclerosis spasticity, AKI induced fibrosis, chronic and neuropathic pain, glaucoma intraocular pressures, and asthma-associated dyspnea.

When researchers antagonized CB2Rs during hypoxia in cardiomyocytes, both inflammation and macrophage digestion were minimized

CB2 receptor is implicated in multiple pathophysiologic processes after heart injury. It modulates inflammatory response, collagen disposition, and organization of stable scar formation.

The CB1 receptor antagonists are cardioprotective against ischemia/reperfusion injury, myocardial ischemia, heart failure, arrhythmias, and cardiomyopathies. The CB1 receptor antagonists also exert beneficial anti-apoptotic, anti-inflammatory, and anti-oxidative actions which are beyond inhibition of CB1-mediated negative inotropic effect Exogenous Cannabinoids

In the US there are three categories of cannabinoids medicines:

single molecule drugs ( and )

cannabis-based liquid extracts (UK drug naximols in trials)

phytocannabinoid botanicals () Research CBD and THC are the most researched cannabinoids. CBD targets CB2Rs with an agonizing effect. The psychotropic affects are minimized as they have very little impact on CB1Rs.

In Colorado researchers manipulated cannabis plant genetics to remove THC in an attempt to develop pediatric epilepsy medication. CBD and THC work better together in a synergistic effects leading to improved outcomes

Charlotte’s web was developed which is high in CBD and low in THC (<0.3%). Maintains better seizure control with minimal psychoactive affects. Theorized that seizures affect the ECS and produce an increased expression of CB1E protein in the hippocampus. Stabilizes potassium and calcium channels inhibiting hyper excitability and seizure activity.

Another drug in development is Epidiolex and being used to treat Dravet’s syndrome a rare form of epilepsy in children between 6 and 10 years old who had failed multiple anticonvulsants.

Medical Cannabis Research

Another study linked CB2Rs to the health and maintenance of kidneys. Animal studies showed decreased kidney fibrosis and renal scarring when CBR1s were blocked in animal with diabetes and kidney disease.

Which of these has more of a hallucinogenic affect? CBD THC Both Medical Cannabis Research Medical cannabis may show promise in the areas of chronic pain and spasticity associated with multiple sclerosis. THC would be used as the primary effector.

CBR1s and cannabinoids in the treatment of PTSD in the veteran population. $2 million dollar grant research project Marijuana for symptoms of PTSD in US Vets

Other researches focused on effects of THC on the treatment of memory loss and Alzheimer’s disease. Animal model demonstrated THC competitively inhibits the acetylcholinesterase and decreases amyloid B-peptide aggregation, a key marker of Alzheimer’s disease.

Conclusion

The Endocannabinoid system could represent a novel pharmacological target in treatment many diseases, however therapeutic use of cannabinoids, their synthetic analogs, and cannabinoid recent agonsits/antagonists remain limited due to their psychotropic adverse affects. It is necessary to develop new compounds without action central nervous system. References

Abel, E.L. (1980). Marijuana, The First Twelve Thousand Years. New York: Plenum Press.

Aso, E., & Ferrer, I. (2014). Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Frontiers in

Pharmacology, 5, 37. http://doi.org/10.3389/fphar.2014.00037

Elena Kaschina (2016). Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function, Cannabinoids in Health and Disease, Prof. Rosaria Meccariello (Ed.), InTech, DOI: 10.5772/62822. Available from: https://www.intechopen.com/books/cannabinoids-in-health-and-disease/cannabinoid-cb1-cb2-receptors-in-the-heart- expression-regulation-and-function