A Pharmacist's Guide to CBD

CBD is a drug, period. You, as a pharmacist, are the community’s drug expert. Naturally, you should be the CBD expert as well.

We learned next to nothing about CBD or our endocannabinoid system in pharmacy school. In fact, the word “cannabidiol” probably isn’t even in the spell-check dictionary on your phone or computer!

However, more than 50 million Americans take CBD every month. Read on to learn what they didn’t teach you in pharmacy school; what you need to know to confidently counsel your customers on CBD.

CBD Belongs in a Pharmacy

There’s a high likelihood that many of your patients and customers are already taking CBD from somewhere, and the CBD they’re buying at a gas station or convenience store is subject to almost no scrutiny regarding safety or dosage. Why would anyone buy CBD from somewhere like that, when they could get it from their pharmacist with whom they already have a trusting relationship.

Most non-pharmacy retail outlet clerks certainly aren’t capable of counseling our patients on a potential adjustment of their warfarin because of interactions it can have with CBD. They don’t even know that our customers are taking warfarin, nor do they have the authority or knowledge to make such a recommendation.

This situation is exacerbated by three main issues:

We weren’t educated on the profound biological activity of CBD or the ECS in pharmacy school.

CBD is stigmatized because of its association with medical marijuana. (CBD IS NOT MEDICAL MARIJUANA!)

The ubiquitous and vital human endocannabinoid system (ECS) has only recently been discovered and researched.

The biggest reason that pharmacists have not been at the forefront of the booming CBD industry is that many of us don’t understand the endocannabinoid system. It is present in nearly every cell of the body, it “regulates regulation” in both the immune system and the nervous system, and there are more cannabinoid receptors in the human body than all other receptor types, combined.

As pharmacists, we need to be fluent when answering questions like:

What is CBD?

How does CBD work?

Why does CBD work?

Why does CBD matter?

What is the endocannabinoid system?

What is CBD?

CBD is an abbreviation for Cannabidiol, a chemical compound found naturally in the cannabis plant. It is not mind altering like THC. CBD will not make you high. Over the past 40 years, there have been numerous studies that highlight the potential benefits of CBD and how it can support the Endocannabinoid System (ECS).

Sublingual CBD Oils are the most popular CBD products, thanks to their high bioavailability and ease of use. Other popular routes of administration include topical salves, gel caps, and gummies.

Importantly, CBD has been found to be well-tolerated even at doses up to 600 MG/day. It was also comparable to placebo in producing no physiological effects at these relatively high doses.

CBD Supplements Our Own Endocannabinoid System (ECS)

Every mammal has an endocannabinoid system (ECS) with receptors throughout their bodies. This system is involved in almost all brain and body functions, from our ability to handle pain, stress, and anxiety to our mobility and muscle health.

 The ECS is a system of G protein-coupled receptors, their several lipid signaling ligands, and the enzymes which synthesize and degrade these signaling molecules. Activation of cannabinoid receptors initiates a second messenger cascade which, in immune cells, inhibits proinflammatory processes, and in neurons, causes polarization and subsequently, reduced likelihood of neurotransmitter release.

NOTE: The statements regarding CBD products have not been completely evaluated by the Food and Drug Administration. CBD products are not intended to diagnose, treat, cure or prevent any disease. Individual results from product usage may vary.

CBD is not Medical Marijuana

If you do any research into CBD on the web, you quickly realize how much confusion exists regarding CBD and medical marijuana.

The misconception that CBD is medical marijuana is one of the most important reasons for educating pharmacists and healthcare professionals – as well as the general public – on the merits and pitfalls of both of these substances.

The biggest difference between CBD and medical marijuana is the presence of THC. THC is the main ingredient in medical marijuana, while hemp-derived CBD products contain undetectable amounts of this psychoactive cannabinoid.

Both of these compounds work via their interaction with the human body’s endocannabinoid system, which “regulates regulation” within the nervous system and the immune system, but that’s where the similarities end.

THC is an agonist at both cannabinoid receptors, and this effect at CBI_ receptors in the brain produces the subjective “high” characteristic of cannabis intoxication. It also leads to internalization of cannabinoid receptors, producing a “tolerance” to the drug as well as altering endogenous cannabinoid function for a period of time even once THC has been excreted.

Medical marijuana typically contains more than 12% THC by dry weight, while hemp-derived CBD products – and all hemp products in general – are defined by containing less than 0.3% THC by weight. This ensures that CBD products don’t make users high, and in fact, they are legally exempted from the definition of marijuana in the Controlled Substances Act.

Furthermore, CBD actually limits the action of THC on CBRs in the body, acting as a “negative allosteric modulator” of CB1 and CB2 receptors. This means it binds to the receptors in a location different from the location where THC and endogenous cannabinoids bind, making them resilient to the effects of agonists.

CBD Mechanisms of Action

CBD has gained notoriety partly because people claim to use it for such a wide variety of conditions. At times, it can seem almost like snake oil in that there’s no way one thing can be useful for so many varied conditions, from arthritis to insomnia. But this is rooted in extensive science and research.

CBD has more than 65 molecular targets in the human body, and for this reason, it has a myriad of different mechanisms of action through which widely varied effects can result. In addition, the endocannabinoid system – which represents its primary targets – is present throughout the entire human body, especially the nervous system and the immune system. By helping the ECS to regulate these two intertwined body systems, as well as interacting with other body systems directly, CBD has a uniquely diverse set of effects.

Endocannabinoid System

CBD acts as a “negative allosteric modulator” of endocannabinoid receptors, which means it binds to a unique location on the receptor, but still reduces the affinity of other ligands to the main binding spot on the receptor. This reduces the ability of endocannabinoid agonists like anandamide or 2-AG as well as phytocannabinoids like THC, to bind to the receptor, therefore reducing the effect they have overall. However, this effect also leads to an upregulation of the CB receptors to compensate for their reduced activity.

Serotonin

CBD acts as a direct agonist of 5-HT1a serotonin receptors, which has a very similar effect to SSRIs on the serotonin system overall; down-regulation and internalization of other post-synaptic 5-HT receptor subtypes. 5-HT1a receptors are presynaptic autoreceptors, so they don’t have a direct effect on downstream neurotransmission, but rather they inhibit upstream neurotransmission which is a prime example of the regulatory effect that cannabinoids have on systems in the human body.

Gene Transcription Factors

One of the most unique actions of CBD in the human body is its interaction with nuclear receptors which regulate the transcription of certain genes. While there are many ways that a chemical can alter the way a cell behaves, altering gene transcription is perhaps the most “behind-the-scenes” form of control. An example which illustrates the utility of this mechanism is CBD’s action on PPAR receptors in the immune system. Activation of these nuclear receptors lead to the increased production of anti-inflammatory genes as well as suppression of proinflammatory genes. Rather than blocking one step in an inflammatory cascade, CBD can actually change the cell’s entire function so the cascade is never initiated in the first place.

TRPV Receptors

TRPVRs – transient receptor potential vanilloid receptors – are found throughout the central and peripheral nervous systems. They are a family of ion channels which act as nociceptors, integral to the perception, transmission, and integration of pain signals in the body as well as the brain. TRPV1 receptors are present in the skin and are receptive to temperatures over 109°F, as well as to capsaicin, the chemical responsible for the burning sensation of chili peppers.

Capsaicin is used as a counter-intuitive pain reliever because of the nature of TRPV receptors. When activated, they rapidly undergo internalization which prevents their further activation. In essence, agonists of TRPV receptors ultimately produce a numbing sensation through inactivation of the receptors. While certain agonists cause a pain response, like capsaicin, CBD is also an agonist, but it doesn’t produce the pain response. For an unknown reason, CBD binds to TRPV1 receptors and causes their internalization without producing a pain response first.

Orphan Receptors

Orphan receptors are those receptors whose structures have been elucidated, but whose physiological role is still unknown. There are hundreds of orphan receptors and slowly as research progresses, their exact function is outlined and they are able to be classified into existing receptor families. Three orphan receptors – GPR18, GPR55, and GPR119 – exhibit CBD binding affinity. These receptors are involved in immune system processes in the body and in glial cells in the brain. As research was done based on this fact, the endogenous ligands of these receptors were discovered, and they happen to be endocannabionid molecules! Not only is this a fruitful area of research into mechanisms of CBD’s action, but it has also advanced discoveries of the body’s own functions as well. Integrated research such as this is already broadening the horizons of drug research and development, and CBD is at the center of it all.

CBD Bioavailability

CBD is a lipophilic substance, and like most hydrophobic drugs, it has very poor oral bioavailability. This is because CBD undergoes extensive first-pass hepatic metabolism. CBD’s low bioavailability has made dosing and delivery a unique challenge for CBD manufacturers in this young industry.

Due to a lack of official FDA guidelines, CBD companies are not permitted to make dosing suggestions or therapeutic claims regarding their products. This has lead to a confusing environment in which patients are left largely to make their own decisions regarding how much, how often, and what kind of CBD to take.

Basic Delivery Methods

Topical

CBD applied topically is the most concentrated way to administer CBD. As a lipophilic substance, CBD tends to accumulate in fatty tissue, and it is very poorly absorbed systemically when administered topically. However, this means that a little goes a long way, as the majority of CBD applied will stay in the location where its applied, making this useful for specific skin, muscle, or joint targets.

Sublingual

CBD absorbed under the tongue is more effective than oral CBD because it is directly taken up into the bloodstream through the sublingual and buccal mucosa, bypassing the extensive first-pass metabolism to which most hydrophobic drugs are subjected. Sublingual CBD products are by far the most popular dosage form because they provide the most “bang for your buck.” By offering higher bioavailability than most non-nano-emulsified ingestible products, they allow an economical amount of CBD to be therapeutically effective.

However, they are messy, don’t always taste good, and are difficult to use. The fact that the user is responsible for sucking exactly the right volume into the dropper leads to inconsistent dosing and waste.

Advanced CBD Delivery Methods

Because of its low bioavailability, there has been a large push to find more efficient routes of administration for CBD products. Nano-emulsification – referring to wrapping a drug molecule in an amphiphilic shell to bypass metabolic enzymes – is leading this charge.

This will allow pills or capsules to become the standard dosage form rather than sublingual oils, which would improve dosage consistency as well as patient adherence, simply because a capsule is easier to consume than a sublingual oil. These developments could fundamentally alter the way CBD is consumed in the future.

The basic premise of advanced delivery methods involves emulsifying CBD within an amphiphilic carrier expressing both hydrophilic and lipophilic domains. The term “nano” refers to the nanoscopic scale of these different domains. The larger the sizes of these domains, the less the bioavailability they provide.

For example, liposomes are hundreds to thousands of nanometers in diameter and millions of cubic nanometers in volume. Compare this to liquid crystal structures with hydrophilic and lipophilic domains mere tens of nanometers away from one another.

Liquid crystalline technology is the clear future of drug delivery methods when it comes to enhanced bioavailability. We will continue to update our various platforms as research in this exciting and fast-paced field continues.

CBD-Drug Interactions

CBD is a drug; As such, there are several inadequately addressed issues facing the CBD industry, the most important of which is the presence of CBD-drug interactions.

Most drug-drug interactions occur when two drugs are metabolized by a single enzyme. The Cytochrome P450 (CYP450) system is responsible for the biotransformation of approximately 85% of all ingested substances, including drugs. As with most proteins, a single substance can be both a substrate (the protein acts on the drug) and an inhibitor/inducer (the drug acts on the protein) of the CYP450 enzymes. We must be equally aware of these influences when considering CBD-drug interactions.

CBD is both a substrate and an inhibitor of CYP3A4 and CYP2C19, but one must consider that it is also an inhibitor of CYP2C9, but not a substrate. Therefore drugs metabolized by CYP3A4 and CVP2C19 can alter the blood levels of CBD, but CBD can alter the blood levels of drugs metabolized by all three enzymes! Because of these complex relationships, only pharmacists should be counseling patients on CBD. Convenience store clerks are simply not qualified to advise people on all of the potential interactions involved with CBD use.

CBD Side Effects

As more research into cannabidiol has been conducted, and better understood, it’s very apparent that it has several mechanisms of action that are similar to the mechanisms of many other legend drugs.

This is at least partially because CBD has more than 65 biological targets in the human body, primarily located throughout the central nervous system and the immune system.

The average pharmaceutical carries with it 70 listed side effects, and while CBD appears to be very safe, it still has some unintended actions that everyone should know about before they take CBD products. As the community pharmacist, who better to educate the community than you?

Just like diphenhydramine is indicated for both allergies and insomnia due to its action on the histamine system in the brain and the immune system, we believe CBD will be indicated for conditions related to the endocannabinoid system, because the ECS regulates so many other organ systems from the brain to the stomach to the skin. However, this means that CBD will have effects in addition to those intended for a given patient, and while they may not be serious or even perceptable, they are still present.

One of the more common side effects of CBD use isn’t actually related to CBD itself, but the oil in which a majority of products are suspended. Both MCT and vegetable glycerin may cause diarrhea because of their oily nature, so this is something that sublingual CBD users should be aware of.

In addition, with much higher dosages, CBD can increase or decrease the action of certain liver enzymes, and it has caused transient hypertension and mild drowsiness as well.

While these aren’t as pronounced as the side effects of many pharmaceutical drugs, they are still real and present and they can cause problems in certain populations. As the community pharmacist, make it your responsibility to find out if your customers are taking CBD, and if so, what side effects they should look for.