THE ENDOCANNABINOID SYSTEM
First, allow us to preface our introduction and description by stating we are not interested in, nor are we advocating the administration of, the well-known psychotropic compound Δ9-tetrahydrocannabinol or Δ9-THC, in concentrations sufficient to produce the ‘high’ or psychotropic effects which are normally associated with marijuana. We are not advocating the administration of marijuana, by any route, in any form, to any animal in order to produce medical benefit or to produce any psychotropic effect.
Rather, we are advocating the administration and continued research into the non-psychotropic compounds called phytocannabinoids, terpenes and flavonoids for the purposes of adjunctive and palliative therapy in companion animals.
In early 2000, we became interested in the well-established and ongoing research from Europe, Canada and Jerusalem concerning the medical benefits derived from the more than 545 identified chemical compounds in Cannabis sativa L., or hemp. More specifically, we were interested in the approximately 111 terpenophenolic compounds named phytocannabinoids, which have not been detected in any other plant, and the more than 140 terpenes and 23 flavonoids produced by Cannabis sativa L. The combination of phytocannabinoids, terpenes and flavonoids has been scientifically demonstrated to modulate numerous physiologic and pathophysiologic processes. This modulation is achieved through the interaction between these compounds and the mammalian endocannabinoid system (ECS).
The ECS consists of four known receptor subtypes, signaling pathways, endogenous ligands (endocannabinoids), EMT and the synthetic and catabolic pathways for said ligands. There are five identified endocannabinoids. The most abundant and deeply researched are 2-arachidonoylglycerol (2-AG) and anandamide. The other lesser understood compounds are Noladin ether, Virodhamine and NADA. These endogenous compounds are classified as neurotransmitters and neuromodulators. Additionally, because these compounds are hydrophobic, their main actions are limited to paracrine and autocrine effects.
The other components of the ECS are numerous G-protein coupled cannabinoid receptors, which CB1-R and CB2-R appear to be the most abundant. The distribution of CB1-R is primarily the CNS, PNS, ANS, pituitary, thyroid, adrenal, male and female reproductive system, hepatic, adipocytes, pulmonary, renal, myocardium, vascular, gastrointestinal neuronal tissue. The distribution of CB2-R is primarily the immune system, spleen, tonsils, thymus, gastrointestinal tract, osteocytes, monocytes, macrophages, microglia, B-cells, T-cells, cerebral cortex, hippocampal pyramidal cells, globus pallidus, cerebellar purkinje cells, cerebellar granual cells, cerebellar nuclei, vestibular nuclei, dorsal motor nucleus of the vagus, nucleus ambiguous, spinal trigeminal, nucleus and spinal sensory neurons.
The final two receptors are newly discovered and the extent of their distribution and effects are currently being researched. CB4-R appears to be predominately located in endothelium and its function is as of yet unknown. CB6-R and its distribution is unclear, but it appears to impart an anti-inflammatory effect which is different from that of CB1-R and CB2-R.
The final components of the ECS are the metabolic and catabolic compounds responsible for production, regulation and degradation of endogenous ligands. A few of these compounds are FAAH, MAGL, DAGL, PLC, Phosphatase, NAPE-PLD, NAPE-PLC and NAT.
Latest research reveals that the endocannabinoid system is ubiquitous in vertebrates and has been discovered in over 50% of invertebrates.
PHYTOCANNABINOIDS
The Cannabis plant contains an enormous variety of naturally occurring compounds. The majority of these compounds are cannabinoids, more specifically phytocannabinoids. To date, 545 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.
The biologically active compounds demonstrate numerous physiologic and pharmacologic effects on multiple mammalian tissues by means of the endocannabinoid system. These effects are achieved by exogenous phytocannabinoids working in concert with endocannabinoids and by imparting those biologic effects directly by means of the ECS. Phytocannabinoids, based upon a plethora of varied factors, interact with the ECS as agonists, partial agonists and antagonists. The variability in this receptor neurotransmitter binding is observed separately and in conjunction with other phytocannabinoids, terpenes and flavonoids. This complicated and established chemical interplay is in part what allows the physiologic modulation of multiple systems by these compounds.
CBC
CBCA
CBD
CBDA
CBDV
CBG
CBGA
CBN l.t. 0.05%
Δ8-THC l.t. 0.01%
Δ9-THC l.t. 0.3%
Δ9-THCA
Δ9-THCV
TERPENES
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 many 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 terpenes in Cannabis display 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 pharmacologic effects directly by means of the endocannabinoid system.
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.
Caryophyllene Oxide
Linalool
Phytol
Limonene
Nerolidol
α-Pinene
FLAVONOIDS
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 plant based compounds are scientifically recognized as one of the largest and most widespread groups of plant secondary metabolites, with marked physiologic properties. Out of the currently 23 identified flavonoids in hemp, only a few have been researched with regards to their biological activity and physiologic effects.
However, even with the limited research, these compounds have demonstrated numerous and wide reaching physiologic effects. The effects are due in part to their interaction with the ECS and their relationship to phytocannabinoids and terpenes. Additionally, they have demonstrated physiologic effects individually and independent of the endocannabinoid system. However, our primary focus is on their interaction with the endocannabinoid system, either individually or in conjunction with the other previously discussed compounds.
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). 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.
Apigenin
β-Sitostero
Cannflavin A & B
Quercetin
USE OF COMPOUNDS
Solving the pharmacologic problem of maximizing the specific benefits of these compounds is accomplished by limiting the Δ9-THC concentration to below 0.3%. This level is far below the psychotropic threshold, while still providing the benefits of Δ9-THC. Δ9-THC is an integral component required for modulating and potentiating the varied array of actions produced by phytocannabinoids, terpenes and flavonoids. 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 effect. Furthermore, the correct dosing of the product 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. Moreover, single compound therapies decrease overall efficacy and in the case of THC, censoriously increase undesired side effects.
The research into these compounds and the beneficial effects are widely available. The amount and variety of research being initiated, investigated, and published is occurring at an ever quickening pace in Europe, Canada, Jerusalem and some 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. We recommend anyone interested in this or similar products investigate, read the research and contact any company selling products containing these compounds before purchase and administration.
A final thought on the intelligent use of phytocannabinoids, terpenes and flavonoids with your pets: these compounds are not a cure-all. They are to be used as directed with any and all currently prescribed medications and therapies, as directed by your attending veterinarian.
Please do not stop or modify any prescribed medications or therapies, unless under the direct supervision of your attending veterinarian.