Amid a global shift toward more natural remedies, a molecule produced by the cannabis plant is experiencing a remarkable rise: cannabidiol, or CBD for short. What was once a neglected component of the hemp plant has, in just a few years, become a beacon of hope for millions of people – from pain sufferers to stressed-out city dwellers. Around the globe, not only is interest growing, but so is the market. Whether in North America, Europe, or Asia: CBD products are conquering pharmacies, online shops, and supermarket shelves.
CBD not only affects the endocannabinoid system
Cannabidiol (CBD) is often discussed in public in connection with its effects on the endocannabinoid system (ECS), but this portrayal is far from accurate. Scientific studies show that CBD, as a "promiscuous" molecule, interacts with at least 15 different pharmacological targets in the human body – including endogenous receptors such as serotonin 5-HT₁A and vanilloid TRPV1, as well as enzymes, ion channels, and other targets. These diverse mechanisms of action make cannabidiol an amazing biological multi-tool. While CBD is often discussed solely in the context of the endocannabinoid system (ECS), it acts not only through this fascinating system – more on the ECS in a moment – but also through many other pathways. Some of the most important pharmacological mechanisms of action of natural CBD in the body involve the following pharmacological targets:
Vanilloid receptors (TRPV1)
CBD binds to our body's TRPV1 receptor—the same sensor responsible for the heat sensation associated with chili peppers (capsaicin). Studies show that CBD activates this channel even at low concentrations, which may explain its pain-modulating effects.
Serotonin receptor 5-HT1A
As a partial agonist of this receptor, CBD influences the serotonin system – a key regulator of mood and stress responses.
PPARγ nuclear receptors
By activating these DNA-binding proteins, CBD could trigger anti-inflammatory and neuroprotective signaling pathways.
GPR55 receptors
CBD blocks this receptor, which is involved in inflammatory processes and bone metabolism.
The endocannabinoid system
But how does CBD also affect the endocannabinoid system? Here, too, the complex and interesting effects of CBD are often presented in a very abbreviated and misleading way. First, let's briefly look at what the endocannabinoid system (ECS) actually is and what functions it performs. The endocannabinoid system is over 500 million years old in evolutionary terms and is found in all animals (except insects) and humans. It is a central component of human physiology and, among other things, plays a key role in maintaining internal balance – so-called homeostasis. The ECS consists of three main components: endocannabinoids (the body's own messenger substances such as anandamide (arachidonylethanolamide, AEA for short), 2-arachidonoylglycerol (2-AG for short), the cannabinoid receptors CB-1 and CB-2, and degrading enzymes such as FAAH (fatty acid amide hydrolase).
CB1 receptors are primarily located in the brain and spinal cord and regulate processes such as pain perception, appetite, memory, and mood. CB2 receptors are found primarily in the immune system and peripheral tissues, but also in various organs and blood-forming cells, among other things, and are involved in inflammatory reactions and immune defense.
A key enzyme in the ECS is FAAH (fatty acid amide hydrolase). It breaks down the endocannabinoid anandamide—a substance often referred to as the "bliss molecule" due to its mood-enhancing effects. (The term "anandamide" is derived from the Sanskrit word "ananda" (आनन्द), which literally means "bliss," "bliss," or "inner happiness.") By inhibiting FAAH, anandamide levels can be increased and thus, for example, stress reduced.
The ECS regulates numerous physiological and psychological processes in the body, including:
Physiological: Pain modulation, anti-inflammatory, sleep-wake rhythm, neuroprotection, digestion and appetite, temperature regulation, hormone balance, immune response, bone formation and regeneration
Psychological: stress management, mood regulation, anxiety processing, reward system, memory formation
The ECS acts like a comprehensive biological "fine-tuning system"—it intervenes wherever balance is lost. Plant cannabinoids such as CBD or THC can exert a variety of effects via this system—but in very different ways.
CBD and THC: Very similar structure, very different effects
While the psychoactive effects of the well-known cannabinoid THC (tetrahydrocannabinol) are primarily explained by its effect on the endocannabinoid system, CBD, as described above, affects many other pharmacological targets in the body and also has a completely different effect on the endocannabinoid system. This is actually surprising, because cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are surprisingly similar at the molecular level: Both have the same molecular formula (C₂₁H₃₀O₂) and almost identical atomic distributions.
The crucial difference, however, lies in their spatial structure—more precisely, in a ring: THC has a closed cyclohexane ring that binds to the CB1 receptor in the brain, triggering the well-known psychoactive effects (the "high"). CBD, on the other hand, has an open side chain at this point. This prevents it from having a direct psychoactive effect and doesn't bind to CB1 in the same way.
Interactions of CBD with the endocannabinoid system
Unlike THC, CBD does not bind directly to the orthosteric (main) binding site of the CB1 receptor, but acts as a negative allosteric modulator . This means that CBD changes the shape of the CB1 receptor at a lateral or allosteric binding site, not at the main binding site for THC. This reduces the binding capacity of THC to CB1 ("negative" effect) – THC can no longer exert its full effect.
Studies show a reduction in THC binding of up to 73%. Receptor signaling (e.g., ERK1/2 activation, dopamine release) is also reduced by up to 60-80%. This could be the mechanism of action behind the observation repeatedly reported by cannabis users that CBD can dampen the psychoactive effects of THC without itself producing a "high."
By the way: although synthetic cannabinoids are molecularly very similar to natural, plant-based cannabinoids, their synthetic modification can result in small structural differences that lead to unpredictable, strong and undesirable pharmacological side effects.
The effect of CBD described above is not the only interesting effect of CBD with regard to its interaction with the mechanism of action of THC in the body. CBD inhibits the enzyme FAAH (fatty acid amide hydrolase), which is responsible for the breakdown of the body's own endocannabinoid anandamide. FAAH inhibition increases anandamide levels in the body, which can promote anxiolytic and mood-stabilizing effects. CBD also indirectly influences THC metabolism: CBD inhibits the body's own CYP450 enzymes, such as CYP3A4 and CYP2C9, which are responsible for the breakdown of THC. This could lead to a delayed breakdown of THC and prolong its duration – albeit with a reduced intensity of the high due to CB1 modulation.
Conclusion
In recent years, cannabidiol (CBD) has evolved from an inconspicuous plant component into a promising therapeutic all-rounder. Its diverse mechanisms of action extend far beyond the well-known endocannabinoid system (ECS). CBD interacts with numerous target structures in the body – including vanilloid and serotonin receptors – and thereby potentially exerts analgesic, mood-enhancing, anti-inflammatory, and neuroprotective effects. However, research on CBD is not yet complete; many effects are currently being investigated in studies and should not be considered proven medical claims.
CBD also exhibits a complex and differentiated action profile in the context of the ECS. Unlike the psychoactive THC, it does not bind directly to the CB1 receptors, but rather acts as an allosteric modulator at the body's endocannabinoid receptor CB-1, potentially weakening the effects of THC. At the same time, it inhibits the enzyme FAAH, which keeps the "happy molecule" anandamide available for longer—a mechanism that may contribute to its stress- and anxiety-relieving effects.
Overall, it can be said that CBD is far more than a natural influence on the endocannabinoid system. It acts as a versatile regulator of physiological and psychological processes, thus opening up a broad spectrum of potential therapeutic applications. This is why cannabidiol is increasingly becoming the focus of modern, holistic medical approaches.
Sources
1. Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, DE, Brandi, I., ... & Di Marzo, V. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology, 134(4), 845-852. https://doi.org/10.1038/sj.bjp.0704327
2. Russo, EB, Burnett, A., Hall, B., & Parker, KK (2005). Agonistic properties of cannabidiol at 5-HT1a receptors. British Journal of Pharmacology, 144(8), 1032-1034. https://doi.org/10.1038/sj.bjp.0706120
3. O'Sullivan, S.E. (2016). An update on PPAR activation by cannabinoids. British Journal of Pharmacology, 173(12), 1899-1910. https://doi.org/10.1111/bph.13497
4. Ryberg, E., Larsson, N., Sjögren, S., Hjorth, S., Hermansson, NO, Leonova, J., ... & Greasley, PJ (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology, 152(7), 1092-1101. https://doi.org/10.1038/sj.bjp.0707460
5. Pertwee, R.G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British Journal of Pharmacology, 153(2), 199-215. https://doi.org/10.1038/sj.bjp.0707442
6. Iannotti, FA, Hill, CL, Leo, A., Alhusaini, A., Soubrane, C., Mazzarella, E., ... & Di Marzo, V. (2014). Non-psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid type 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. British Journal of Pharmacology, 171(8), 2426-2441. https://doi.org/10.1111/bph.12534
7. Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. International Journal of Molecular Sciences, 19(3), 833. https://doi.org/10.3390/ijms19030833
8. Di Marzo, V., Bifulco, M., & De Petrocellis, L. (2004). The endocannabinoid system and its therapeutic exploitation. Nature Reviews Drug Discovery, 3(9), 771-784. https://doi.org/10.1038/nrd1495
9. Mechoulam, R., Parker, L.A., & Gallily, R. (2002). Cannabidiol: an overview of some pharmacological aspects. Journal of Clinical Pharmacology, 42(11 Suppl), 11S-19S. https://doi.org/10.1177/00912700222011409
10. Laprairie, RB, Bagher, AM, Kelly, ME, & Denovan-Wright, EM (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British Journal of Pharmacology, 172(20), 4790-4805. https://doi.org/10.1111/bph.13250
11. Yamaori, S., Okamoto, Y., Yamamoto, I., & Watanabe, K. (2011). Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2C19. Drug Metabolism and Pharmacokinetics, 26(6), 554-560. https://doi.org/10.2133/dmpk.DMPK-11-RG-061
12. Devinsky, O., Cross, JH, Laux, L., Marsh, E., Miller, I., Nabbout, R., ... & Friedman, D. (2017). Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine, 376(21), 2011-2020. https://doi.org/10.1056/NEJMoa1611618
13. Hill, MN, & Gorzalka, BB (2009). The endocannabinoid system and the treatment of mood and anxiety disorders. CNS & Neurological Disorders-Drug Targets, 8(6), 451-458. https://doi.org/10.2174/187152709789824660
14. Zuardi, A. W. (2008). Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira de Psiquiatria, 30(3), 271-280. https://doi.org/10.1590/S1516-44462008000300015
15. Atalay, S., Jarocka-Karpowicz, I., & Skrzydlewska, E. (2019). Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants, 9(1), 21. https://doi.org/10.3390/antiox9010021
Author: Dr. Sebastian Marincolo