MORE on Cannabinoids and Cannabidiol (CBD)

Cynthia Lan Sears, MS, CHES 


CBD molecule


In 2002 Maurice Elphick of Queen Mary University in London presented his research at the annual meeting of the Society for Experimental Biology. Elphick had previously ​demonstrated that the cannabinoid system in mammals "is a fundamental signalling system in the central nervous system of vertebrates, where it plays a role in movement, pain, and learning and memory.” The 2002 presentation built on his previous work. He had discovered cannabinoid receptors outside of the nervous system among invertebrates, specifically sea squirts. This means that the receptor for cannabinoids existed much earlier in the evolutionary line than previously estimated. Cannabinoids have served a biological function in animals since invertebrates evolved (Genomeweb, 2002).

The Endocannabinoid System 

The endocannabinoid system is the largest neurotransmitter system in the brain. This system can be affected either by cannabinoids from outside of the body (exogenous), or those produced by the body itself (endogenous). THC was first isolated in 1964, but the endocannabinoid system wasn’t mapped until 1992 (Bearman, 2017). This was due partly to the restrictions placed on scientific research associated with cannabis and all its associated compounds. Policymakers’ assumptions based on the lack of endogenous alcohol receptors in the brain led to the mistaken assumption that cannabinoids were similar kinds of intoxicants.

Knowledge about the role of the endocannabinoid system is still evolving, but the available evidence suggests that this system has multiple regulatory roles in neuronal, vascular, metabolic, immune, and reproductive systems (Atakan, 2012). There are at least two types of cannabinoid receptors in mammalian tissues, CB1 and CB2 receptors. CB1 receptors are in the brain and spinal cord as well as peripheral tissues further from the central nervous system. CB2 receptors are found primarily in immune tissues. There are no CB1 receptors in the brain stem, which governs the essential physiological functioning of the human body; this is thought to explain the complete absence of overdose-related death. The brain stem functions are unaffected by cannabinoid overdose (Sears, 2017).

Endocannabinoids are crucial to bio-regulation of a wide range of physiological systems, including inflammation, insulin sensitivity, and fat and energy metabolism. Modulation of the endocannabinoid system may provide more effective treatments for chronic neurologic and immune dysfunction. Their main role is in cell-signaling, and, because they are hydrophobic (rather than hydrophilic), their main actions are not systemic; rather, they are localized to
paracrine (cell-to-cell) or autocrine (same cell) effects (Griffing, 2018). Essentially, the structure of endocannabinoids is such that their actions tend to be localized.

Cannabinoids are commonly known for being densely available on the cannabis plant. Most of the cannabinoids from cannabis plants that have been studied have demonstrated therapeutic value, as have the terpenes, which give the plant its distinct odors. As of this writing, there are over 125 terpenes and over 80 cannabinoids in cannabis that have been identified, and each strain has its own unique blend that create its distinct effects.

Cannabidiol (CBD) was formerly regarded as devoid of pharmacological activity due to the intense focus on THC, and the fact that CBD lacks the euphoric effects seen with THC. While CBD is not psychotropic, it is psychoactive, meaning that it crosses the blood-brain barrier. CBD can be administered at much higher doses than THC with no negative psychiatric side-effects.

Therapeutic Applications of CBD 

Seizure Disorders

Of the milestones for CBD research in 2017 was GW Pharmaceuticals passing phase three clinical trials for Epidiolex, a pure cannabidiol extract designed to treat pediatric epilepsy. Scientific evidence is placed on a hierarchy, and controlled clinical trial research is considered the “gold standard” of evidence due to the rigor with which the studies must be designed, methodology used, and the number of participants required.

The most adverse effects reported involved diarrhea and drowsiness, but it’s notable that among the group treated with CBD, 5% of patients experienced a complete cessation of seizure activity, while none in the placebo group experienced remission. The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (Devinksy et al, 2017). It should be noted that other countries, such as Brazil, have already approved CBD as a treatment for epilepsy.

Charlotte’s Web is a unique strain of medical marijuana, arguably be one of the strains that is most strongly associated with CBD, due to the fact that it is one of the few that has an almost nonexistent THC content. This strain was developed crossing traditional high-THC cannabis with industrial hemp plants that have a nearly nonexistent THC content. Cannabis plants usually demonstrate an inverse relationship between CBD and THC content: the higher the THC content, as is seen in boutique strains bred for recreational purposes, the lower the CBD content and vice versa.

Antipsychotic Effects 

Zuardi and colleagues (2012) conducted a critical review of the antipsychotic effects of CBD spanning a 30 year time period and concluded that CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs using behavioral and neurochemical techniques in animal models, with a minimal side effect profile. The mechanism of action was not fully understood at that time. Subsequent work by Schubart and colleagues (2014), and Iseger and Bossong in 2015 (including the first small-scale clinical trials of application with schizophrenia), upheld the conclusions by Zuardi.

Researchers concluded that CBD was useful in treating psychosis, and specifically in THC-induced psychosis. Researchers theorized that effects are mediated by opposing effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex (Iseger and Bosson, 2015).

Anxiolytic (anti-anxiety) Effects 

While THC can notoriously induce anxiety and paranoia, CBD’s anxiolytic effects were observed in animal studies as early as 1990 (​Guimaraes et al, 1990). ​In human models the method of action for CBD effective in treating anxiety stems from activity in limbic and paralimbic brain areas (Crippa et al, 2011). Similarly, ​Bergamaschi and colleagues (2011) found that CBD reduced public speaking-related anxiety among social phobia patients who had not previously undergone behavioral therapy.

Atakan (2012) identified a wide range of anxiolytic pharmacological actions associated with CBD and THC, and cautioned that street cannabis, because it is not regulated and often features strains bred for a high THC-content, does not produce the same specificity of pharmacological action. More broadly, Blessing and colleagues (2015) concluded that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, they caution that further longitudinal data on long-term use is needed for useful application in practice.

Multiple Sclerosis  

In Europe, many multiple sclerosis (MS) patients are prescribed nabiximols, or Sativex, to mediate the severity of spasticity, a condition that causes the muscles to continuously contract. THC and CBD help regulate neurotransmitters that are affected in patients with MS and a
successful clinical trial of Sativex showed that about 75% of MS patients saw improvements from the cannabis-based medicine (Flachenecker, Henze, & Zettl, 2014).

Additional cannabinoids being researched for a therapeutic potential: 

With the popular hyperfocus on CBD, there has been less press given to other cannabinoids beyond THC that are being examined for potential isolation and pharmaceutical application.

● Cannabichomene (CBC) has demonstrated anti-inflammatory and pain reducing effects in animal experiments. 
● Cannabigerol (CBG) only weakly binds to CB1 and CB2 receptors. This cannabinoid has also been demonstrated to have pain relieving, anti-depressive and cancer-inhibiting properties. 
● Tetrahydrocannabivarin (THCV) is a cannabinoid of the delta-9-THC-type, which in low doses can block the CB1 receptor, rather than stimulate it. Inhibition of the actions of this cannabinoid could be used to reduce appetite among patients who require pharmaceutical appetite control.

Takeaways 

The discussion of CBD in this article has focused on the therapeutic applications that have been clarified in medical and pharmacological research. Beyond the therapeutic applications, it’s important to note that CBD has also been associated with improved quality of life in chronic and acute disease processes such as Parkinson’s Disease, Cancer, and HIV/AIDS. Medically, the positive effects can be tied to the anti-inflammatory, anti-nausea, and anxiolytic effects of CBD. In the effort to assess the quality of treatments from the perspective of mortality, the alleviation of disability and associated suffering, while more difficult to quantify, is also crucial to maintain awareness of due to the fact that ​how​ patients live in their remaining days is almost as important as how ​many days they continue to live.




References 

Atakan, Z. (2012). Cannabis, a complex plant: different compounds and different effects on individuals. Therapeutic advances in psychopharmacology, 2(6), 241-254. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736954/pdf/10.1177_2045125312457586.pdf 

Bearman, D. (2017). A Primer About Cannabidiol And The Benefits Of CBD. https://www.huffingtonpost.com/entry/cannabidiol-cbd-a-primer_us_58b7129ee4b0ddf65424629 0

Bergamaschi, M. M., Queiroz, R. H. C., Chagas, M. H. N., De Oliveira, D. C. G., De Martinis, B. S., Kapczinski, F., ... & Martín-Santos, R. (2011). Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology, 36(6), 1219. ​https://www.ncbi.nlm.nih.gov/pubmed/21307846

Blessing, E. M., Steenkamp, M. M., Manzanares, J., & Marmar, C. R. (2015). Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics, 12(4), 825-836. https://www.ncbi.nlm.nih.gov/pubmed/26341731

Chagas, M. H. N., Zuardi, A. W., Tumas, V., Pena-Pereira, M. A., Sobreira, E. T., Bergamaschi, M. M., ... & Crippa, J. A. S. (2014). Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. Journal of Psychopharmacology, 28(11), 1088-1098. ​https://www.ncbi.nlm.nih.gov/pubmed/25237116

Crippa, J. A. S., Derenusson, G. N., Ferrari, T. B., Wichert-Ana, L., Duran, F. L., Martin-Santos, R., ... & Filho, A. S. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25(1), 121-130. ​https://www.ncbi.nlm.nih.gov/pubmed/20829306

Devinsky, O., Cross, J. H., Laux, L., Marsh, E., Miller, I., Nabbout, R., ... & Wright, S. (2017). Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine, 376(21), 2011-2020. http://www.nejm.org/doi/full/10.1056/NEJMoa1611618#t=article 

Flachenecker, P., Henze, T., & Zettl, U. K. (2014). Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice-results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. European neurology, 71(5-6), 271-279. https://www.ncbi.nlm.nih.gov/pubmed/24525548

Genomeweb (2002). Sea Squirt Genome Reveals Cannabinoid Receptor Older Than Believed. https://www.genomeweb.com/archive/sea-squirt-genome-reveals-cannabinoid-receptor-older-bel ieved

Griffing, G. (2018). Endocannabinoids. https://emedicine.medscape.com/article/1361971-overview

 Guimaraes, F. S., Chiaretti, T. M., Graeff, F. G., & Zuardi, A. W. (1990). Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology, 100(4), 558-559. https://www.ncbi.nlm.nih.gov/pubmed/1969666

Iseger, T. A., & Bossong, M. G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia research, 162(1), 153-161. https://www.ncbi.nlm.nih.gov/pubmed/25667194

Reggente, N. (2016). Charlotte’s Web: The definitive medical marijuana strain. https://learn.woahstork.com/strains/charlottes-web-strain-of-cannabis/

Schubart, C. D., Sommer, I. E. C., Fusar-Poli, P., De Witte, L., Kahn, R. S., & Boks, M. P. M. (2014). Cannabidiol as a potential treatment for psychosis. European Neuropsychopharmacology, 24(1), 51-64. ​https://www.ncbi.nlm.nih.gov/pubmed/24309088/

Sears, CL. (2017). The Endocannabinoid System and Therapeutic Use of Medical Cannabis, THC and CBD. ​http://www.milkandequity.com/2017/03/the-endocannabinoid-system-and.html

Zuardi, A., Crippa, A. S., EC Hallak, J., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., McGuire, P. & Silveira Guimaraes, F. (2012). A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Translational Investigation. Current Pharmaceutical Design, 18(32), 5131-5140. ​https://www.ncbi.nlm.nih.gov/pubmed/22716160

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