"Cannabis" is commonly used in legal and lay language to describe plants that would fall under the legal classification of "marijuana": a plant with THC concentrations greater than 0.3%. However, cannabis is a term that technically can be used to describe any plant in the genus Cannabis sativa L. within the Cannabaceae family, which includes plants known as hemp, ruderalis, and marijuana.
What is a veterinary cannabis “expert”?
That is truly a question that needs better consensus. Like most mainstream hot topic issues or industries, the term “expert” gets bastardized pretty quickly, since there are no set standards or accrediting bodies to call someone a cannabis expert. Please read this article if you are trying to find reliable sources of information in regard to cannabis education.
The endocannabinoid system is a system comprised of naturally occurring ligands (called endocannabinoids), catabolic and hydrolyzing enzymes, receptors CB1 and CB2, and other endocannabinoid-like molecules. The function of the ECS is vast but is commonly known to maintain homeostasis and has been implicated as a treatment target for nearly every disease process.
There has recently been an expansion of the ECS that includes other receptors and ligands known collectively as the endocannabinoidome. This expansion includes a new understanding that the affinity of endogenous ligands and other exogenous molecules from the cannabis plant (known as phytocannabinoids) also have affinity for other receptors we may be more familiar with such as opioid, dopamine, serotonin, TRPV, and several other receptor types. This speaks to the interest in using phytocannabinoids for several conditions.
To put it simply, the entourage effect is a synergy or potentiation of various cannabinoids, terpenes, flavonoids and other phenolics or alkaloids when used together. This is similar to creating a multi-modal anesthetic or analgesic plan. The entourage effect can occur with naturally occurring endogenous ligands or exogenous compounds. The entourage effect does not necessarily correlate with action at the ECS receptors.
ECS tonicity is the sensitivity of the ECS based on a number of factors. These include the number of ECS receptors available and their proliferation during disease or imbalance, the amount of catalyzing or hydrolyzing enzymes for production of endocannabinoids, actual circulation and production of endocannabinoids, ECS/endocannabinoidome receptor variants and overall health.
ECS deficiency describes the body's imbalance between the production of endocannabinoids and expression of ECS receptors which can lead to several clinical manifestations. This deficiency syndrome is now being assessed in animals as well.
Endocannabinoid- "like" ligands
Endocannabinoids are created within the body as signaling messengers primarily with the CB1 and CB2 receptors. They are created on demand and degraded (hydrolyzed) into various other more familiar chemical messengers such as oxytocin, serotonin and archadonic acid. The chart below outlines some of the more common endocannabinoids.
Phytocannabinoids are created by plants that can act not only on the ECS receptors but many other receptors. They can be manipulated during processing into various other types of phytocannabinoids such as CBD to THC, or THC to CBN. There are over 125 different phytocannabinoids described in the literature with a majority of research focusing on only 8.
"Cannabinoid" as a word is used interchangeably in reference to plant derived compounds, endogenously produced compounds or compounds synthesized in the lab.
Other cannabinoid-like compounds have been described that are created within the body and are also able to be synthesized. Common cannabinoid-like compounds are palmitoylethanolamid (PEA) and oleoylethanolamide (OEA)
Microscopic view of a bubble of phytocannabinoids and other cannabis derived compounds excreted through a trichome on the flower of a cannabis plant.
Chart showing the 5 more common phytocannabinoids and their natural production. There are over 125 phytocannabinoids not described in the literature, each with their own therapeutic benefits.
Terpenes are molecules that create the distinctive aroma of cannabis in all its forms. Terpenes have their own therapeutic value and have been used for centuries. They are also known as "essential oils". Terpenes are classified as GRAS (generally referred to as safe) compounds by the FDA. While their effects are still being explored, terpenes have a synergistic and supportive effect with cannabinoids.
Flavonoids create the color profile of various plants. More and more research is being conducted looking at the therapeutic effects of these compounds, particularly for cancer treatment.
Fatty acids, in particular Omega-3's have long been known to play a critical role in health. They are also the building blocks for endocannabinoids. The cannabis plant produces a number of fatty acids.
Common terpenes found in cannabis plants
There is some contention surrounding the definitive definitions of each of these types of products. However, we use definitions that are not meant to up-sell or create a narrative manufacturers have been trying to propagate.
Ideally, broad spectrum products are those that use a majority of the compounds found in the plant, whether that is from hemp or marijuana. During extraction, intentional or not, specific phytocannabinoids may be lost or removed. The same is true for terpenes. With broad spectrum products the entourage effect can occur. Manufacturers are attempting to define broad spectrum as "THC Free" or products that contain only a couple cannabinoids or terpenes. While this could technically be true, we consider products with only a few compounds "limited spectrum" products.
A full spectrum product is one that contains all the phytocannabinoids and terpenes the plants have to offer- or spiked. Some purests define these as products that also use hemp seed oil as the carrier for the compounds. These are our preferred products to use not only because of their potential for a more pronounced entourage effect, but also often require lower dosing compared to broad or isolate products.
Isolate products are heavily refined that contain only a single cannabinoid. Currently, the only FDA approved plant derived cannabinoid product is an isolate known as Epidiolex.
Certificate of Analysis (COA)
All over the counter phytocannabinoid products, like all animal supplements, are not FDA approved. This brings concerns as to the quality of products and what is actually in them. So far, the best option for veterinary professionals and pet parents is to ask the manufacturer of a particular product for a COA for the same batch number of product you have. If the company is not willing to give a full COA, like the example below we suggest finding a different product.
In a study published in 2020, the researchers found many products whose label phytocannabinoid profile did not match what was actually in the product. Even more alarming a few products had unsafe levels of lead and arsenic.
A COA is not only useful for assessing the quality of the product but also dosing and expected outcomes based on the phytocannabinoid and terpene profile.
COA's should be from a third party lab that is ISO/IEC 17025 certified. The COA should be for the final product, not the biomass sample and contain at minimum the phytocannabinoids listed in this profile above.
A complete COA should have what is known as an elemental analysis which will show potentially dangerous heavy metal contamination. A complete COA should also have a microbiological, pathogenic bacterial and mycotoxin (mold) contaminant analysis. Cannabis plants are known for their good phytoremediation. This means the plants are very good at picking up whatever is in the soil around them. In fact, hemp plants are intentionally used in areas of heavy pollution to clean the soil. This behavior however can lead to heavily contaminated products that could be unsafe for consumption.
A complete COA should have a pesticide, fungicide and residual solvent (volatile organic compounds) analysis. This is particularly important since the compounds being used are harvested from the outside of the plant in a sticky resin. This sticky resist can trap these chemicals and lead to a contaminated product. Until federal standards are established we prefer labs that stick to the allowable reference ranges set by the state of California and Massachusetts as they are the most stringent.
Finally, a COA should have a terpene analysis. Depending on the terpene profile, even in the phytocannabinoid profiles are the same, we can expect much different clinical outcomes. If you are expecting therapeutic benefits from terpenes we typically like to see concentrations greater that 0.05% total, and not to exceed 2%. While we believe in the benefits of terpenes is should be noted these are often the limiting factor for compliant admonition and tolerability of dosing for animals.
Dosing can be quite nuanced as every product seems to have a different phytocannabinoid or terpene profile. Thus far, several studies show safety and efficacy with wide ranges in dosing and with short and longe term use.
Phytocannabinoid containing products are not a one size fits all option. Depending on the specific condition and makeup of a product recommendations can vary greatly. We recommend reading the open access papers on the Resources page or the Cannabis Therapy in Veterinary Medicine textbook to better understand using these product safely.
We prefer the term "Intoxication" to "Toxicity"
The consumption of phytocannabinoids does induce liver enzyme changes. This means that using things like CBD may change the efficacy and pharmacokinetics of other concurrent medications that rely on the same specific cytochrome P450 enzymes phytocannabinoids alter. In the veterinary studies at hand this appears to be a more theoretical concern. Phenobarbital is a common concurrent medication given with CBD. Two studies show little concern. NSAIDS and gabapentin with concurrent CBD has also been published with not concerns.
Trazodone serum concentrations are altered with concurrent CBD administration but did not present a clinical concern. However, any SSRI taken in combination with cannabinoid containing products may increase chances of serotonin syndrome- although human and animal literature fails to provide any case reports. Medications that are prominent substrates for CYP2C19, CYP2C9, CYP3A4 and CYP1A2 may be particularly at risk of altered disposition by concomitant use
The most common drug interaction appears to be transient lethargy when given with tramadol, acepromazine, gabapentin, phenobarbital.
Profound behavioral changes or THC intoxication like symptoms are noted when cannabinoids are mixed with benzodiazepines, even when isolates are used containing no THC. Dosing adjustments are advised.
Monitoring patients while on a product
For animals that will be on a phytocannabinoid product for >3months, we recommend a pre-administration blood chemistry, in addition to monitoring blood chemistry profiles every 3-6 months.
Multiple studies have shown elevations in alkaline phosphatase (ALP) in dogs and a random increase of alanine aminotransferase (ALT) in one cat. These do not cause immediate concern unless the values are >5x the high end reference range.
For animals on a CBD product that are undergoing an elective procedure we recommend stopping the product at least 3 days prior to the procedure and CBD has been shown to increase blood clotting times.
*We are currently in the midst of a study assessing the seriousness and source of ALP elevations in dogs.