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Introduction

Cannabis, also known as marijuana, is a flowering plant recognized for its medicinal and recreational uses. Cannabis acts on the endocannbinoid system, a system of endogenous receptors that may have a mediating role in inflammation, nausea, pain, and many other biological functions.

Cannabis has over 80 chemical constituents, known as “cannabinoids”, which alter neurotransmitter release from the brain1. Two of the most active and studied constituents of cannabis are tetrahydrocannabinol (“THC”) and cannabidiol (“CBD”). THC is the major psychoactive component of cannabis. CBD acts on many of the same receptors as THC, but without the psychoactive side effects. Recent evidence suggests that CBD has potential therapeutic benefits for a wide range of conditions2.

Structure of CBD

History

Cannabis has been cultivated for its medicinal, psychoactive, and physical properties for thousands of years. The earliest recorded medicinal uses of the plant date as far back as 1400-2000 BC. In the 19th century, William Osler, credited for creating the first residency program and considered to be a “Father of Modern Medicine”, was a proponent of the medicinal use of cannabis. He believed the plant was an effective treatment for migraines.

By 1937, the “Marijuana Tax Act” was passed, representing the U.S. government’s first step toward regulating and taxing the production of hemp and marijuana for industrial and medicinal purposes3. However, the Act was ruled unconstitutional in 1969 and marijuana was criminalized shortly after. As a result, research into the medicinal qualities of marijuana was effectively halted for many years.

CBD was first discovered by Dr. Roger Adams and his team at the University of Illinois in 19404; however, its structure was not fully elucidated until 19635. While CBD was discovered more than 20 years before THC, THC has dominated cannabis research until recently6.

Scientific Literature Indexed by PubMed

Attracted by its low toxicity and early proof of efficacy, the mainstream medical establishment has begun to actively explore the use of cannabinoids for a variety of ailments.

Mechanism of Action

CBD exerts its actions through a variety of pathways. One site of action is the endocannabinoid system, a system of receptors found in the brain, central and peripheral nervous systems, fat, muscle, and immune cells. Naturally occurring substances called “endocannabinoids” and the cannabinoids found in marijuana are major effectors on this system.

THC is a strong activator of the endocannabinoid system while CBD has a weaker activation impact on the system, but its mechanism of action is more complicated. Both THC and CBD bind to the endocannabinoid receptor called CB1. By weakly binding CB1 receptor, CBD is thought to inhibit the release of glutamate, an excitatory neurotransmitter7. This is important because the inhibitory actions of the CB1 receptor play a role in maintaining normal brain activity – CB1 receptors protect the brain against seizures8.

Through its interactions with the endocannabinoid system, CBD may counteract many of the psychological and physiological effects of THC9. Additionally, CBD increases levels of an endocannabinoid called anandamine, which creates anti-inflammatory effects through its activation of cannabinoid receptors10.

Another biochemical target of CBD is the transient receptor potential (“TRP”) class of channels. These channels affect the levels of calcium within the cell. The action of CBD at these receptors can increase calcium levels in a number of different types of cells11.

CBD also increases signaling of the 5HT-1A serotonin receptor12. Serotonin is a chemical found in the body that regulates mood balance. Serotonin system dysfunction is associated with a variety of disorders, including depression. Many antidepressants work by increasing serotonin levels in the brain13. The actions of CBD at serotonin receptors have been associated with decreasing anxiety and protecting brain cells from death.

CBD has been shown to protect the brain from damage due to oxidative stress, decreased brain inflammation, and increased levels of a neurotransmitter called adenosine, a molecule important for energy creation and sleep regulation. Each of these effects has the potential to offer therapeutic benefits14.

CB1 receptors are primarily found in the brain and central nervous system and to a lesser extent in other tissues. CB2 receptors are primarily found in the peripheral organs, especially cells associated with the immune system.

Pharmacokinetics

CBD can enter the body through various routes – the most studied are inhalation (by smoking cannabis recreationally or for medicinal purposes) and orally. The route of administration determines the “bioavailability” of CBD, the proportion of the drug that enters circulation when introduced that is able to have an active effect.

Based on the observation that CBD is effective when inhaled, the bioavailability of CBD has been studied using devices to vaporize or aerosolize the substance. Using these methods, some studies have measured bioavailability of approximately 31% of the administered dose. This is a high bioavailability, but this route of administration requires specialized equipment to aerosolize or vaporize the CBD, which can be costly and difficult for patients to use15.

Oral administration is an easier way to deliver CBD, but it suffers from drawbacks as well. Since any drug taken orally must pass through the liver before entering systemic circulation, there is a risk that the substance will be completely broken down into inactive molecules before it can have a therapeutic effect on the patient. In the case of CBD, only 6% of the dose that is administered makes it through the liver unaltered16. Additionally, in vitro evidence suggests that orally administered CBD may be degraded into THC by the contents of the stomach17.

Alternate methods of administration are being investigated, including delivery through a transdermal patch. However, CBD is highly lipophilic – meaning it is more soluble in fat than in aqueous solutions – which makes it challenging to prevent the accumulation of the drug in the skin18.

Given the drawbacks of current administration methods, there is clear potential for improved formulations and delivery methods that could increase the bioavailability of CBD while decreasing the production of undesirable metabolites. Furthermore, CBD has a half-life of 18 to 32 hours, which may offer opportunities to improve the activity of CBD by slowing its degradation19.

Proprietary Prodrugs

Kalytera is developing a new class of proprietary CBD therapeutics. CBD is a remarkable compound that has shown activity against a number of pharmacological targets. However, there are limitations associated with natural CBD, including its poor oral bioavailability and short half-life.

Kalytera is developing innovative CBD formulations and prodrugs in an effort to overcome these limitations, and to target specific disease sites within the body. Kalytera has filed composition of matter and method of use patents covering its novel inventions, with the goal of limiting future competition. Learn more >>

References

  1. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389-462.
  2. Mechoulam R, Peters M, Murillo-rodriguez E, Hanus LO. Cannabidiol–recent advances. Chem Biodivers. 2007;4(8):1678-92.
  3. Baron EP. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache. 2015;55(6):885-916.
  4. http://pubs.acs.org/doi/abs/10.1021/ja01858a058
  5. Michoulam R, Shvo Y. Hashish. I. The structure of cannabidiol. Tetrahedron. 1963;19(12):2073-8.
  6. http://pubs.acs.org/doi/abs/10.1021/ja01062a046
  7. Welty TE, Luebke A, Gidal BE. Cannabidiol: promise and pitfalls. Epilepsy Curr. 2014;14(5):250-2.
  8. Wallace R. Cannabinoids: defending the epileptic brain. Epilepsy Curr. 2004;4(3):93-5.
  9. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234-46.
  10. Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016;30(11):3682-3689.
  11. Welty TE, Luebke A, Gidal BE. Cannabidiol: promise and pitfalls. Epilepsy Curr. 2014;14(5):250-2.
  12. Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119-127.
  13. Blier P, De montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994;15(7):220-6.
  14. Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119-127.
  15. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.
  16. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.
  17. https://online.liebertpub.com/doi/pdf/10.1089/can.2015.0004
  18. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.
  19. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.

Recent Press Releases

Kalytera Announces Initiation of Phase 2 Clinical Study in Prevention of Graft Versus Host Disease and Agreement with The Salzman Group of Israel to Manage and Partially Fund the Study to be Led by a World Class Team

By | GvHD, Press Release
Kalytera Therapeutics, Inc. (TSX-V:KALY) and (OTCQB:KALTF) (the "Company" or "Kalytera") today announced the initiation of a Phase 2 clinical study evaluating the use of cannabidiol ("CBD") in the prevention of graft versus host disease ("GVHD"). Kalytera also announced today that...
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