Understanding the Endocannabinoid System

The endocannabinoid system (ECS) was formally identified in the early 1990s by Dr. Raphael Mechoulam and colleagues at Hebrew University, following the isolation of THC in 1964. The CB1 receptor was cloned in 1990, CB2 in 1993, and the first endocannabinoid — anandamide — was characterized in 1992. The ECS is a retrograde neuromodulatory system present in virtually all vertebrates, regulating homeostasis across the nervous, immune, and endocrine systems. Its late discovery (relative to other receptor systems) explains why it is not covered in most medical and allied health curricula — a gap that practitioners are increasingly working to address.

No. The ECS is primarily activated by endocannabinoids — lipid-based neurotransmitters produced by the body itself. The two primary endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Phytocannabinoids from cannabis (CBD, THC, CBG, etc.) interact with the same receptor system, but the ECS functions continuously in the absence of any plant-derived compounds. Other compounds that modulate ECS activity include certain terpenes (beta-caryophyllene is a CB2 agonist), omega-3 fatty acids (precursors to endocannabinoids), and some flavonoids.

CB1 receptors are primarily expressed in the central nervous system — brain, spinal cord, and peripheral sensory neurons. They are responsible for the psychoactive effects of THC. CB2 receptors are predominantly expressed in peripheral tissue: skin keratinocytes, mast cells, immune cells, bone, and synovial tissue. For topical applications, CB2 is the primary target. Because topical cannabinoids do not reach systemic circulation in clinically meaningful concentrations, CB1-mediated psychoactivity is not a concern — making topical formulations appropriate for patients who need to avoid any CNS effects.

CBD does not directly activate CB1 receptors at typical concentrations — it acts as a negative allosteric modulator, meaning it reduces CB1 receptor activity rather than stimulating it. Psychoactivity requires direct CB1 agonism (as THC produces). CBD’s primary mechanisms — FAAH inhibition, TRPV1 modulation, PPARγ agonism — do not involve direct CB1 activation. Additionally, when applied topically, CBD does not reach the CNS in concentrations sufficient to produce any systemic effect, further eliminating any psychoactivity concern.

The entourage effect was first described by Mechoulam and Ben-Shabat in 1998 and refers to the synergistic interaction between cannabinoids, terpenes, and other hemp-derived compounds. The hypothesis proposes that whole-plant extracts produce greater therapeutic effects than isolated compounds at equivalent doses. Supporting evidence includes a 2011 review by Russo (British Journal of Pharmacology) demonstrating that terpene-cannabinoid combinations modulate receptor activity in ways that isolated cannabinoids do not. For topical applications, the practical implication is that full-spectrum formulations — which preserve the complete cannabinoid and terpene profile — are expected to outperform CBD isolate products for most clinical applications.

The key distinction is mechanism of action. CBD primarily works indirectly — through FAAH inhibition, TRPV1 modulation, and negative allosteric modulation of CB1. CBG is a direct partial agonist at both CB1 and CB2 receptors, giving it a more conventional pharmacological profile. For topical applications, CBG’s direct CB2 agonism is particularly relevant — it engages the primary peripheral receptor more directly than CBD does. The two cannabinoids are complementary rather than redundant: CBD amplifies endocannabinoid tone via FAAH inhibition while CBG directly activates CB2. This is the rationale behind Kannaco’s 1:1 CBD:CBG ratio.

Standard drug tests screen for THC metabolites (specifically 11-nor-9-carboxy-THC, or THC-COOH), which are produced when THC is metabolized systemically. Topical cannabinoids do not reach systemic circulation in meaningful concentrations and therefore do not produce THC metabolites detectable by standard urine immunoassay tests. Kannaco’s formulations contain less than 0.3% THC by dry weight (compliant with the 2018 Farm Bill). For patients subject to drug testing — athletes, military personnel, or those in regulated professions — topical application is the lowest-risk route of cannabinoid administration. Practitioners should still advise patients to review their specific testing program requirements.

Oral CBD is a known inhibitor of cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2C19), which can affect the metabolism of medications including warfarin, clobazam, and certain statins. However, topical CBD does not reach systemic circulation in concentrations sufficient to produce clinically relevant CYP450 inhibition. The drug interaction risk associated with oral CBD does not apply to topical formulations. Practitioners should still exercise standard clinical judgment for patients on narrow therapeutic index medications, and advise patients to disclose all topical products to their prescribing physicians.

Start with physiology, not the product. Explain that the body produces its own cannabinoid-like molecules (anandamide and 2-AG) that regulate inflammation, sensation, and tissue homeostasis — and that CBD and CBG work by supporting this existing system, not by introducing a foreign mechanism. Emphasize that topical application means the compounds stay local — they do not enter the bloodstream, do not affect the brain, and do not produce any psychoactive effect. Framing the recommendation as "supporting your body’s own regulatory system at the site of discomfort" tends to resonate more with skeptical patients than product-focused language.

PubMed (pubmed.ncbi.nlm.nih.gov) is the primary database for peer-reviewed ECS and cannabinoid research. Key search terms include "endocannabinoid system," "cannabidiol topical," "CB2 receptor skin," and "cannabigerol." Foundational papers include Mechoulam & Ben-Shabat (1998) on the entourage effect, Russo (2011) on terpene-cannabinoid interactions, and Tóth et al. (2019) on the cutaneous ECS. The International Cannabinoid Research Society (ICRS) and the Society of Cannabis Clinicians also publish practitioner-oriented resources. Kannaco’s Practitioner Downloads page provides curated reference documents and patient education materials for your practice.