How does CBD work? The Endocannabinoid System and The Entourage Effect
The Endocannabinoid System
A brief history
By the 1970s, researchers were rapidly expanding our understanding of neurotransmitters and receptor systems in the brain. Neurotransmitters are “the messengers that relay information between neurons throughout the entirety of the nervous system.” Neuroreceptors are specialized protein molecules present in cell membranes which are activated by neurotransmitters, allowing communication through chemical signals.
By 1973, researchers had identified receptor sites in the brain capable of binding with opioids. CBD: A Patient’s Guide to Medicinal Cannabis¹ suggests they may have discovered similar receptors for cannabis soon after, had their efforts not been stunted by a politicized agenda surrounding cannabis research.
In 1992, researchers discovered that the human body naturally produces its own cannabinoid-like compounds, later named endocannabinoids, which are similar to the plant-based phytocannabinoids present in hemp and cannabis.¹
What does the endocannabinoid system do?
Researchers have determined that two main receptors in the body (CB1 and CB2) respond similarly to endocannabinoids produced naturally in the body as they do to plant-based phytocannabinoids.
Current research suggests that the endocannabinoid system plays an important role in regulating pleasure, energy, mood, appetite, pain signaling, inflammation, stress response, and overall well-being. It also appears to help the body maintain homeostasis, or internal balance, in the face of injury and disease.¹
Healthline writes that research has linked the endocannabinoid system to a wide range of bodily functions, all of which contribute to homeostasis, which refers to the stability of your internal environment. “For example, if an outside force, such as pain from an injury or a fever, throws off your body’s homeostasis, your ECS kicks in to help your body return to its ideal operation.” (Healthline)
What happens when we consume CBD?
“All cannabinoids produce effects in the body by interacting with cannabinoid receptors, which form part of the endocannabinoid system.” (medicalnewstoday.com)
Our current understanding of the endocannabinoid system is that it consists of the following:
Two receptors
CB1: coordinates movement, pain, emotion, mood, thinking, appetite, memory, and other neurological functions.
CB2: primarily affects inflammation, immune response, and pain signaling.
Two signaling molecules
Arachidonoyl Ethanolamide (AEA or anandamide) & 2-arachidonoyl glycerol (2-AG)
Five enzymes
DGLα (for synthesis of 2-AG), DGLβ (for synthesis of 2-AG), NAPE selective phospholipase-D (for synthesis of AEA), MAGL (for breakdown of 2-AG), FAAH (for breakdown of AEA).¹
According to an article published in the British Journal of Pharmacology, THC is a CB1 and CB2 agonist. This means THC binds directly to cannabinoid receptors in the body and mimics some of the function and role of naturally occurring endocannabinoids. (weedmaps.com)
CBD interacts with the endocannabinoid system differently. Unlike THC, CBD does not strongly bind directly to CB1 receptors. Researchers believe CBD influences the endocannabinoid system more indirectly by affecting receptor activity and influencing how the body regulates its own endocannabinoids. CBD is also thought to counteract some of the effects produced by THC. (weedmaps.com)
This difference in how THC and CBD interact with cannabinoid receptors helps explain why they feel so different. THC has a more intoxicating and psychoactive effect because it binds more directly to cannabinoid receptors. CBD, meanwhile, is generally considered non-intoxicating, meaning it does not produce the “high” associated with THC, though it may still influence mood, stress response, pain signaling, and other neurological functions.
Can you take too much CBD?
There are currently no documented deaths directly caused by THC or CBD toxicity alone. Research suggests that it is extraordinarily difficult to reach a lethal dose of cannabinoids because cannabinoid receptors are not concentrated in the brainstem regions responsible for controlling breathing and other vital functions. (potguide.com)
In a separate article, potguide.com elaborates: “Preliminary studies show that marijuana has a therapeutic index (the ratio that compares the blood concentration at which a drug becomes toxic versus effective) of 40,000:1.” Comparatively, Morphine has a therapeutic index of 70:1.
That said, consuming too much THC can absolutely still produce unpleasant or distressing experiences including anxiety, paranoia, dizziness, nausea, rapid heart rate, and confusion — particularly in inexperienced users or at very high doses.
The Entourage Effect
One of the primary features of phytocannabinoids (plant-based cannabinoids unique to cannabis) is that many researchers and consumers believe they work better in whole-plant extracts than they do as isolated, refined, or synthesized compounds. This theory is commonly referred to as the “entourage effect,” though it is still being actively researched.
CBD: A Patient’s Guide To Medical Cannabis¹ explains:
“THC has psychotropic effects that are partially modified and significantly decreased when paired with CBD. A study² regarding the use of cannabis in patients with moderate to severe spasticity due to multiple sclerosis suggests that 1:1 THC/CBD is more effective than either isolated CBD or isolated THC. In another study,³ ‘high THC in a plant extract reversed the actual disease progression of multiple sclerosis, but CBD in a plant extract did not do so.’ In a third study,⁴ isolated CBD was consistently shown to have a narrow dose range, below which or above which it was ineffective for the treatment of pain and inflammation. Meanwhile, CBD-enriched whole-plant extract with very low levels of THC, CBC, CBG, CBN and CBDV improved as a pain reliever and anti-inflammatory as the dose was increased and was far more effective than pure CBD. ‘In effect, THC acts as a catalyst that makes CBD work better.’”
This is why Full Spectrum CBD products are often recommended for people who are not concerned about drug testing. It is also why a great deal of medicinal cannabis literature recommends using CBD and THC in conjunction with one another. There are many different ways to use both CBD and THC, so there’s something for nearly everyone.
Terms:
Psychotropic: “Denotes a pharmacotherapeutic agent that affects brain function, usually used in the context of drugs.” (thefreedictionary.com)
Endocannabinoid System: “The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults… The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids.” (ncbi.nlm.nih.gov)
Endocannabinoids: “a naturally occurring neuromodulatory lipid in the body involved in the regulation of numerous physical systems”¹
Phytocannabinoids: cannabinoids which are unique to cannabis plants¹
CB1 (cannabinoid-1) receptor: “believed to be located primarily in the central and peripheral nervous system, activated by all types of cannabinoids and largely responsible for the efficacy of THC”¹
CB2 (cannabinoid-2) receptor: “believed to be located primarily in the peripheral tissues of the immune system, the gastrointestinal system, the peripheral nervous system, and to a lesser degree in the central nervous system.”¹
Sources:
Leinow, Leonard, Juliana Birnbaum, and Michael H. Moskowitz, “CBD: A Patient's Guide to Medicinal Cannabis,” North Atlantic, 2017.
Y. Y. Syed, K. McKeage, and L. J. Scott, “Delta-9-tetrahydrocannabinol/cannabidiol (Sativex): A Review of Its Use in Patients with Moderate to Severe Spasticity Due to Multiple Sclerosis,” Drugs 74, no. 5 (April 2014): 563-578.
M. Moreno-Martet, A. Feliu, F. Espejo-Porras, M. Mecha, F.J. Carrillo-Salinas, J. Fernandez-Ruiz, C. Guaza, and E. de Lago, “The Disease-Modifying Effects of a Sativex-Like Combination of Phytocannabinoids in Mice with Experimental Autoimmune Encephalomyelitis Are Preferentially Due to Delta-9-tetrahydrocannabinol Acting through CB1,” Multiple Sclerosis Related Disorders 6 (November 4, 2015): 505-511.
R. Gallily, Z. Yekhtin, and L. O. Hanus, “Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol.” Pharmacology & Pharmacy 6 (2015): 75-85.
