Part V: CBD Oil… Hype, Harm, or Heck Yeah!

A Brief Overview

Due to the many aspects of this nationally acclaimed “magical medical elixir,” my series on CBD (cannabidiol) oil has weaved through a variety of subtopics. These included:

-a brief introduction to CBD oil and some of its precautions

-a history of the use and legal restrictions of the cannabis plant, of which its constituent, CBD, is extracted

a review of CBD oil’s current medical indications

-re-clarifying the state and federal laws related to CBD oil after the passage of the Farm Bill that legalized hemp

-an introduction to the difference between CBD oil extract and cannabis essential oil (see clarification below)

In this article, I am going to provide an overview of the mechanisms of actions of the many compounds found in cannabis, including CBD. I will be starting with reviewing the system that many of its constituents interact with, the endocannabinoid system.

Before we get into the “weeds” of the cannabinoids, we’ll first walk down terpene lane with cannabis essential oil.


CBD oil vs. Cannabis Essential Oil

In answering the question of whether CBD oil was an essential oil in my recent video, I misspoke. I stated it correctly in the original article, but also posted a clarification on the video blog page. Below is the excerpt:

Most of the CBD oil in the U.S. is not technically the “essential oil of CBD.” CBD is a constituent in cannabis, you cannot extract an essential oil from a compound. CBD oil has different extraction methods than steam distilled essential oils. (source, source) This link provides a basic explanation for the most common type, fatty oil extraction.

According to Robert Tisserand, an internationally respected essential oils expert, there is a steam distilled CANNABIS essential oil available in Canada, Switzerland, and France.

I previously mentioned the importance of the “entourage effect” of cannabis. This term references the idea that the whole spectrum extract of hemp or cannabis will be more effective than any of its isolated compounds alone or any select mix of its constituents. For this reason, many formulators advertise their hemp oil or CBD product to contain additional cannabinoids from the plant along with its essential oils (mostly in the form of terpenes).

In a future post, I will discuss more details about the properties of the cannabis essential oil constituents in the clinical applications of the full spectrum plant.

Now, I will start my promised review of the literature on the actions of CBD and the various compounds found in cannabis. In order to fully understand their effects, it’s important to have knowledge of the endocannabinoid system, in which its cannabinoids and some of its other constituents modulate.

The Endocannabinoid System (ECS)

The endocannabinoid system (ECS) is an underappreciated regulator of a variety of biochemical processes. The body produces its own (endogenous) endocannabinoids that affect many of its central and peripheral responses. A dysregulation in the ECS is linked to various disorders. (source, source, source, source, source)

The ECS was not well studied until the discovery of different drugs and compounds that were found to impact its cannabinoid receptors. The most famous is delta-9-THC (tetrahydrocannabinol), the psychoactive component in cannabis. (source, source, source, source)

Several other compounds and medications can affect cannabinoid receptors in a variety of ways. For example, I previously discussed that a compound in copaiba, beta-caryophyllene, has evidence of binding to one of the cannabinoid receptors in the body that does not act as a psychoactive, rather it has other beneficial effects.

A 2009 abstract provides a good summary of the ECS and how its endogenous endocannabinoids (eCB) are released, transported, and degraded within the body. eCB act through a unique form of retrograde signaling within the neurons. This results in a wide-spread response, impacting the whole central nervous system. (source, source)

For those who want the biochemistry, the mentioned abstract states (bold emphasis mine):

Endocannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)…

The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions…

In the 2017 article, Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting, the authors further detail the effects of endocannabinoids (eCBs). They also highlight the two main cannabinoid receptors and the endogenous and synthetic  compounds that act as their modulators.

In the following excerpt, I emphasized in bold the key points in the article for those who want to skip through the alphabet soup of physiology and aim for a more basic understanding:

eCBs and Disease

Endocannabinoids (eCBs) and their receptors are found throughout the human body: nervous system, internal organs, connective tissues, glands, and immune cells. The eCB system has a homeostatic role, having been characterized as “eat, sleep, relax, forget, and protect.”26 It is known that eCBs have a role in the pathology of many disorders while also serving a protective function in certain medical conditions.27 It has been proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent clinical eCB deficiency syndromes (CEDS). Deficiencies in eCB signaling could be also involved in the pathogenesis of depression. In human studies, eCB system deficiencies have been implicated in schizophrenia, multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease, anorexia, chronic motion sickness, and failure to thrive in infants.28


Cannabinoid Receptors

The eCB system represents a microcosm of psycho-neuroimmunology or “mind–body” medicine. The eCB system consists of receptors, endogenous ligands, and ligand metabolic enzymes. A variety of physiological processes occur when cannabinoid receptors are stimulated.

Cannabinoid receptor type 1 (CB1) is the most abundant G-protein–coupled receptor. It is expressed in the central nervous system, with particularly dense expression in (ranked in order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala.

CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, connective and musculoskeletal tissues, and the gonads.

CB2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system.


The “Entourage” of the Endogenous (AEA, 2-AG) eCB and Phytocannabinoids (THC and CBD)

The excerpt below is a little complicated for the non-chemist and me.

For those who want plain English and to skip through the science, here’s the summary: The endogenous cannabinoids can work with delta-9-THC and CBD to influence receptors throughout the body. Various “entourage” compounds, such as fatty acid amides, can also enhance effects.

For those who want “geek speak,” I highlighted the main points in bold.

The most well-known eCB ligands are N-arachidonyl-ethanolamide (anandamide or AEA) and sn-2-arachidonoyl-glycerol (2-AG). AEA and 2-AG are released upon demand from cell membrane phospholipid precursors. This “classic” eCB system has expanded with the discovery of secondary receptors, ligands, and ligand metabolic enzymes.

 For example, AEA, 2-AG, N-arachidonoyl glycine (NAGly), and the phytocannabinoids- delta-9-THC and CBD may also serve, to different extents, as ligands at GPR55, GPR18, GPR119, and several transient receptor potential ion channels (e.g., TRPV1, TRPV2, TRPA1, TRPM8) that have actions similar to capsaicin.28

The effects of AEA and 2-AG can be enhanced by “entourage compounds” that inhibit their hydrolysis via substrate competition, and thereby prolong their action through synergy and augmentation. Entourage compounds include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA), and cis-9-octadecenoamide (OEA or oleamide) and may represent a novel route for molecular regulation of endogenous cannabinoid activity.29



Okay, take a breath!

Below is a breakdown:

  1. We’ve learned that our body produces its own cannabinoids and they effect our nervous system and other processes in unique ways.

  2. Other compounds, natural and/or synthetic can act on these same receptors, or modulate them, to enhance and balance out their effects.

Onto the next article.


Contrasting CBD with THC

In an article that explored the ECS and its role in multiple sclerosis (MS), the authors provided an overview on the compounds of cannabis, its cannabinoids, and an exploration of their mechanisms. They also differentiate that although THC hits the cannabinoid receptors, CB1 and CB2, CBD does not. CBD does; however, have an impact on many other receptors. They state that THC and CBD have been found to be anti-inflammatory and relieve pain.

The authors also explain CB1 regulates brain functioning and plasticity and pain. CB2’s exact role is controversial, but it may impact brain inflammation and has been found in the mitochondria and intracellularly.

Below is an excerpt if you want more details (bold emphasis mine):

For over 5000 years, Cannabis (Cannabis sativa) has long been used for recreational and medicinal purposes for more than 5000 years. Cannabis extracts like marijuana contain more than 500 natural compounds, out of which over 110 belong to cannabinoids (Maccarrone et al., 2017).

Although the first isolated plant-derived cannabinoids were cannabinol and cannabidiol (CBD), the identification of the major psychoactive constituent THC was achieved later on (Table 1) (Adams, 1942, Gaoni and Mechoulam, 1964), establishing the current field of cannabinoid research

Several cannabinoids have distinct biological activity, yet THC and CBD were particularly studied due to their broad spectrum of action, including analgesic and anti-inflammatory effects. THC stereoselectively acts in the CNS (Mechoulam et al., 1988) by binding to a specific target identified as the type-1 cannabinoid receptor (CB1) (Devane et al., 1988)…

Few years later a type-2 cannabinoid receptor (CB2) was discovered in peripheral B- and T-lymphocytes (Munro et al., 1993). THC binds to both CB1 and CB2 with high affinity (Huffman, 2000, Mahadevan et al., 2000), whereas CBD, a non-psychoactive component, shows little affinity for both receptors (Mechoulam et al., 2007). Upon activation both receptors inhibit the formation of the second messenger cAMP, and modulate other signal transduction pathways such as extracellular regulated kinases, B-arrestin, and ion channels…

There is a debate on the expression levels of CB1 and CB2 in different cell types and its subcellular localisation, but there is a general consensus that CB1 is widely expressed within the CNS in cortical neurons and interneurons, astrocytes, oligodendrocytes and oligodendrocyte precursor cells, as well as in several leukocytes infiltrating the brain (Navarrete and Araque, 2010, Galve-Roperh et al., 2013).

CB1 regulates cognitive, memory and motor functions as well as analgesia and synaptic plasticity.

On the contrary, the expression of CB2 in cells of the CNS is more controversial, inasmuch as its presence for a long time was exclusively associated to microglia, but more recently it was also documented in brainstem neurons and astrocytes upon cellular activation by an insult or inflammation (Van Sickle et al., 2005; Onaivi et al., 2006; Atwood and Mackie, 2010; et al., 2015a, 2015b; et al., 2015a, 2015b). Furthermore, a substantial proportion of CB1 in the brain is intracellular, being found in vesicles (Leterrier et al., 2004), mitochondria (Bénard et al., 2012) or lysosomes (Rozenfeld and Devi, 2008). Interestingly, the human brain has more CB1 than any other G protein-coupled receptor.

A Sneak Peak on Clinical Trials with Cannabinoid Medications

In a mega-long, monstrous review from 2008, The Endocannabinoid System as an Emerging Target of Pharmacotherapy, all things related to the topic of ECS and cannabinoids were highlighted. It is a great resource for the nitty-gritty details on the cannabinoid receptors, synthetic and endogenous cannabinoids, and these compounds’ role in health and disease. They even provide outcomes from all types of human trials! If you want to take three to four hours of your time to really get the biochemistry down, this is a source to bookmark.

For those looking for the cliff notes, again, I’ve got you covered.

The article gives an exquisite overview on the clinical trials using cannabinoid-related medications, including THC and CBD, for neurological diseases, pain, metabolic dysfunction, gastrointestinal issues, and immune disorders. You can view the table here that summarizes the outcomes of using cannabinoid-related medications by disease!


Article Summary

Now that we have seen how the ECS influences our body and that cannabis compounds impact it, we have an insight into why they have such diverse effects!

We’ve highlighted the psychoactive constituent THC and its effects based on the cannabinoid receptors it hits. We are also aware that CBD works by a different mechanism, yet both have anti-inflammatory and pain relieving properties.

Finally, I provided a sneak peak on outcome-based clinical trials for cannabinoid-related medications in diseases!

Coming up, I will highlight more research and clinical trials using CBD. I will also explore the benefits of the “entourage effect.”

Stay with me!

Feel free to post your comments below!

This material is for information purposes only and is not intended to diagnose, treat, or prescribe for any illness. You should check with your doctor regarding implementing any new strategies into your wellness regime. These statements have not been evaluated by the FDA. (Affiliation link.)

Disclaimer: This information is applicable ONLY for therapeutic quality essential oils. This information DOES NOT apply to essential oils that have not been tested for purity and standardized constituents. There is no quality control in the United States, and oils labeled as “100% pure” need only to contain 5% of the actual oil. The rest of the bottle can be filled with fillers and sometimes toxic ingredients that can irritate the skin. The studies are not based solely on a specific brand of an essential oil, unless stated. Please read the full study for more information.

Thanks Pixabay