CBD: MECHANISM OF ACTION 4 KEY CONSIDERATIONS FOR COMPOUND: Cannabidiol (CBD) CBD has multiple molecular targets that extend beyond the classical cannabinoid receptors. CBD is one of approximately 100 phytocannabinoids naturally occurring in hemp plants. Cannabinoids By inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades anandamide, CBD SELECTING QUALITY CBD refer to molecules found in the cannabis plant that interact with cannabinoid receptors. Common activates cannabinoid receptors indirectly. cannabinoids include: D9-THC, THCV, CBD, CBDV, CBG and CBC. THC-free — non- Solvent-free, clean

detectable and every C02 extraction batch tested Fatty Acid Amide Hydrolase GPR55 KEY FACTS: Understanding the ECS inhibition receptor inhibition 100% US-sourced, IC ~10 –20µM 50 IC <0.5µM UNDERSTANDING • Plays vital neurological and immunomodulatory roles that can affect overall health 50 CBD Colloidal delivery field-grown agricultural FAAH systems for enhanced hemp • Comprised of specialized eicosanoids, known as endocannabinoids, that the body makes from THE ENDOCANNABINOID lipid precursors bioavailability

Anandamide PPARγ SYSTEM (ECS) activation EC50 = 5µM 1. 2. 3. Adenosine reuptake inhibition High-quality CBD products provide a high-potency dosage per

IC 50 <5µM capsule, broad-spectrum support from phytocannabinoids, CBCB1 CB2 gluten-free CB1, CB 2 beta-caryophyllene and other terpenes, and are Legend receptor Low-affinity interaction supported by and non-GMO. activation limited/inconclusive data Endocannabinoids Cannabinoid Enzymes TRPV1 Low-to moderate-affinity interaction 1. Anandamide Receptors that control Vanilloid receptor supported by satisfactory data 5HT1A endocannabinoid activation/ 2. 2-Arachidonoylglycerol (2-AG) Serotonin receptor Potent interaction supported by levels activation desensitization satisfactory data EC 50 <5µM EC 50 = 0.007µM DOUGLAS L A B O R A T O R I E S ©2019 Douglas Laboratories. DOUGLAS L A B O R A T O R I E S

DLQFHM519 All rights reserved. THE ECS IN THE CNS THE ECS IN THE PERIPHERY INFLUENCE ON SEROTONIN IMPORTANCE OF ENHANCED The two major endocannabinoids — anandamide and 2-AG — activate two different cannabinoid The CB receptor is located primarily in the gut, immune system, and periphery, where it modulates the 2 SIGNALING BIOAVAILABILITY receptors: CB1 and CB2. The CB1 receptor is primarily expressed on neurons in the brain and immune response and downregulates the production of cytokines, such as IL-6, IL-1β, TNFα, IFNβ, and IFNγ. nervous systems; a main function is to inhibit excitatory neurotransmission. The levels of anandamide and 2-AG are tightly controlled by the balance of synthesis and degradation. • Colloidal delivery systems: water-soluble Water-soluble colloidal droplets allow even dispersion of CBD and droplets cross the intestinal CBD facilitates neurotransmission water layer for better terpenes in the GI tract absorption. Presynaptic neuron mediated by the serotonin 5HT1A In cells of the immune system, receptor. • Droplets easily cross the water layer at the Once activated, the CB1 receptor Anandamide or 2-AG 1 3 GI tract, and other peripheral tissues, intestinal brush border, a major absorption WATER LAYER inhibits further release of the (endocannabinoids) stimulating neurotransmitter, endocannabinoids (primarily 2-AG) activate obstacle for lipophilic compounds Anandamide or 2-AG eliciting a relaxant effect. CB2 receptors. MUCOSA While cannabidiol (endocannabinoids) Beta-caryophyllene CB supports endocannabinoid signaling indirectly, BLOODSTREAM 1 Excitatory neurotransmitter Inflammatory cytokines beta-caryophyllene (eg. glutamate) (e.g. TNF-α, IL-6, IFNγ) is a direct CB2 agonist, Endocannabinoids potentially sharing similar 2 CB1 activate CB1 receptors, immunomodulating effects CBD has poor bioavailability CB2 which are located on as the endocannabinoids. due to its lipophilic properties. the presynaptic neuron. More research is needed to explore this effect in humans. The intestinal brush border is coated with a Once activated, CB2 water layer, which normally limits the absorption 2 receptors elicit many of fat-soluble compounds. Enclosing CBD and CBD increases levels of the endocannabinoid immunomodulating 1 Excitatory neurotransmitters anandamide by inhibiting its reuptake and activate endocannabinoid effects, which depend terpenes in a water-soluble droplet improves degradation. As a result, more anandamide synthesis and release. on the cell type and is available to activate cannabinoid receptors. Neurotransmitter its environment. the uptake of these bioactives across the water receptor layer, allowing better absorption. The enzyme that CBD modulates is known as FAAH.

CB2 activation modifies 3 Endocannabinoid inflammatory cytokine production, which has In the limbic system of the ENZYMES synthesis NERVE STIMULATION broad clinical implications. brain, activation of this receptor contributes to calming effects. Improving water solubility with a colloidal Postsynaptic neuron Degradation technology greatly enhances absorption and To learn more visit increases plasma levels of CBD. douglaslabs.com