The Cannabis plant contains an enormous variety of naturally occurring chemical compounds. The majority are cannabinoids, more specifically phytocannabinoids. To date, 545 total compounds have been identified, including 111 phytocannabinoids, which are unique to Cannabis sativa L. The term cannabinoid represents a group of C21 terpenophenolic compounds, their carboxylic acids, analogs and transformation products. It is important to note some of the identified phytocannabinoids in Cannabis are biologically active, others are not. The most researched phytocannabinoids, or exogenous cannabinoids, to date are: CBD, CBG, CBC, CBN, CBDA, CBGA, CBCA, CBDV, Δ9-THCA, Δ9-THCV, Δ8-THC, and Δ9-THC.
As discussed, these bioactive compounds demonstrate numerous physiologic and pharmacologic effects on multiple tissues via the ECS. These effects are achieved by administering exogenous phytocannabinoids which work in concert with endocannabinoids and impart physiologic effects either directly or indirectly via the ECS. Phytocannabinoids, based upon a plethora of varied factors, interact with the ECS as either agonists, inverse agonists or antagonists.
eCB and exogenous phytocannabinoids potentiate and or mitigate each other, when given in a ratioed combination. Moreover, the endogenous cannabinoid effects are exponentially increased by administration of ratioed exogenous phytocannabinoids, terpenes and flavonoids. The variability in receptor pharmacologic response is primarily based upon concentration, ratio and compounds present. This complicated and scientifically established chemical interplay is in part what allows the physiologic modulation of multiple systems by these compounds.
Phytocannabinoids are just part of the chemical equation. Terpenes are the main building blocks of any plant resin or essential oil. They contribute to the scent, flavor and color of plants. Terpenes represent a large class of aromatic organic hydrocarbons structurally related to isoprene and are produced by numerous species of plants. The isoprene unit forms monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids. These compounds are referred to as terpenoids when denatured by oxidation, as when drying and curing flowers.
The 120 terpenes in Cannabis impart an extensive range of biological activities, which are involved in potentiating and mitigating the effects of phytocannabinoids, other terpenes and flavonoids, as well as producing their own unique primary pharmacologic effects by means of the endocannabinoid system. Additionally, they impart physiologic modulation via interaction with other receptor systems. However, our primary focus is their interaction with the ECS, either independently or in conjunction with the other previously discussed endogenous and exogenous compounds.
Terpenes are and have been commonly incorporated into pulmonary medicines, such as bronchial inhalers and cough suppressants.
The following is a list of the some of the terpenes found in some Cannabis sativa L. strains.
Flavonoids have become popular in nutrition and medicine for their antioxidant benefits. They often occur as the pigments in fruits and flowers. Flavonoids are aromatic polyphenolic compounds with a common chemical structure existing mainly as C-/O- and O-glycosides of the flavon- and flavonol- type aglycones. Several sub classes exist based upon variation of that base chemical structure.
In Cannabis sativa L., more than 23 flavonoids have been identified, representing seven chemical structures which can be glycosylated, prenylated or methylated. These compounds are scientifically recognized as one of the largest and most widespread groups of plant based secondary metabolites with marked physiologic effects. Out of the currently 23 identified flavonoids in hemp, only a few have been researched with regards to their physiologic activity.
However, even with limited research, these compounds have demonstrated numerous and wide reaching physiologic properties. They directly interact with and modulate the ECS. Furthermore, they chemically potentiate and mitigate the physiologic activity of phytocannabinoids and terpenes. Similarly, they have demonstrated physiologic modulation individually and independent of the endocannabinoid system.
A common flavonoid, not related to hemp but used as a medication for years, is rutin. Rutin is a citrus derived flavonoid from the Fava D’Anta tree (Dimorphandra mollis), as well as several other sources. It is used as an adjunctive therapy for idiopathic chylothorax and hypercholesterolemia.
The following is a list of the some of the flavonoids found in some Cannabis sativa L. strains.
Solving the pharmacologic problem of maximizing the specific and combined benefits of these compounds is accomplished by limiting the Δ9-THC concentration to below 0.3%. This level is far below the psychotropic threshold, which is 1.0% to 1.5%, while still providing the numerous specific benefits associated with Δ9-THC. Δ9-THC is an integral component required for mitigating and potentiating the varied array of physiologic activities produced by phytocannabinoids, terpenes and flavonoids. Similarly, Δ9-THC imparts its own benefits, which are potentiated by coadministration as discussed.
Additionally, the hemp strains used and the ratio of the specific phytocannabinoids, terpenes and flavonoids in the final product are critical in achieving and maximizing the desired physiologic effects. Furthermore, the correct administration recommendations based on the animals’ medical history, age, weight and severity of pathophysiology is crucial. Phytocannabinoids, terpenes and flavonoids are significantly less effective when they are used in a ‘one size fits all’ approach or are administered as a single compound, such as in a CBD only formulation.
Single compound therapies narrow the therapeutic range, decrease overall efficacy and in the case of THC, CBD CBN or CBG only products, substantially increase undesired side effects. These pharmacodynamic results are dose and time dependent but can be significant. As stated previously, research has shifted over the last decade to reveal low dose ratioed compound therapies offer the widest therapeutic range, provide more consistency and cause fewer adverse effects.
The research into these compounds and their beneficial effects is widely available. We recommend focusing on the countries detailed, as they have been involved in this specific research for decades. The amount and variety of research initiated, investigated, and published, is occurring at an ever-quickening pace in Europe, Canada, Israel and several Asian countries. Even the Unites States of America, with its three-quarter century prohibition of Cannabis and the semi-moratorium on Cannabis research, including hemp, is starting to shift its policies.
In this country, we are experiencing the beginning of the end of prohibition. This fluid transition period, as history reveals, is often fraught with ambiguity, over regulation and unclear legal directives. This rapidly evolving state will persist for some time but will eventually find homeostasis and we can join the other countries who enjoy the freedom to use and research the endless potential these compounds hold. We recommend anyone interested in our or similar products investigate, read the research and contact the company selling products containing these compounds before purchase and administration. Education is crucial in eradicating the misapplication, misinformation and fear concerning these compounds.
A note on the misconceptions surrounding Δ9-THC toxicity and sensitivity. For those who are concerned with Δ9-THC toxicity, we recommend researching LD50 information on the following species: mice, rat, canine and primate in oral, intravenous and intraperitoneal dosage forms, as this information is readily available and is not necessary to reiterate in this overview. Concerning Δ9-THC sensitivity, as it relates to a proposed increase of CB1R concentration in specific areas of the canine brain. Variation within species exists, it is inherent and integral. However, this variation does not inevitably equate to lowered toxicity threshold.
This proposed species variation, which might lead to a change in exogenous compound sensitivity, is compensated for pharmacodynamically. Such compensation is a constant with any pharmacologic therapy and is one of the scientific principles which provides for dose ranges. We have administered Δ9-THC, with other phytocannabinoids, terpenes and flavonoids to numerous species for nearly 15 years. Over that time, we have not observed any increased sensitivity or toxicity issues, as they relate to extended duration administration of Δ9-THC. Δ9-THC has a role and should be used intelligently, adjusting according to the principles of pharmacokinetics and pharmacodynamics, as with any administered compound.
Some final thoughts on the intelligent use of phytocannabinoids, terpenes and flavonoids with your patients and companions: these compounds are not a cure-all. They are to be used as directed with all currently prescribed medications and therapies, as directed by your attending veterinarian.
Additionally, the industry is new and highly unregulated. This translates into product inconsistency and potential toxicities from compounds and opportunistic organisms. These include, pesticides, herbicides, hydrocarbon or solvent residues, heavy metals, fungal, mold and microbial contamination. Toxic hydrocarbons, like butane, naphthalene, toluene and acetone, are sometimes used during the extraction process, and can end up in final products as residual solvents. They should not be administered to animals. Currently, the cleanest extraction method is either supercritical CO2 or subcritical CO2 extraction. This method leaves behind no residual solvents. Additional potential contaminations include microbial, fungal and mold. A COA should document the product is free from these contaminates as well.
A simple way to avoid these contaminations and potential health consequences, is for you or your client to request a certificate of analysis (COA) on the product from the company with which they are interested in purchasing. A COA should include measurements of the concentration of compound(s) contained in the product and is provided in either percentage or mg. Furthermore, a complete COA should confirm the product is free from contamination from the deleterious compounds detailed above. This is currently the only protection a consumer can utilize to ensure they are purchasing and using a consistent and clean product in their companions. There are plenty of companies who will readily provide a COA upon request. If a company will not provide a COA, for whatever reason, we would recommend finding one who will.
*Please do not stop or modify any prescribed medications or therapies, unless under the direct supervision of your attending veterinarian.