By Daniel Gana, MsC, Abraham Benavides, MD, and Brent Ristow, PhD, JD, 2-18-2025

Cannabinoids are some of nature’s most impressive biochemical keys, each designed to unlock specific molecular locks within the human body. Just as a key fits into a lock to open a door, cannabinoids bind to receptors in the endocannabinoid system (ECS), each initiating a wide array of biological responses.

Cannabinoids And The ECS

The Endocannabinoid System (ECS) is a finely tuned security system within the body, designed to maintain balance and overall well-being. It consists of receptors, including CB1 and CB2, which act as locks, while cannabinoids (endocannabinoids and phytocannabinoids) serve as the natural keys. The body produces its own cannabinoids, known as endocannabinoids, such as anandamide and 2-AG, which help regulate essential functions like pain, mood, and inflammation. See our previous article for a list of other endocannabinoids. 

When cannabinoids from hemp (phytocannabinoids) interact with these receptors, they mimic the function of the body’s own endocannabinoids, influencing everything from pain perception and inflammation to mood regulation and neuroprotection. This interaction plays a pivotal role in maintaining homeostasis and promoting balance within various bodily systems.

However, the influence of cannabinoids goes beyond the CB1 and CB2 receptors. Just like a master key can open multiple doors, cannabinoids unlock various health benefits, including improved sleep, reduced anxiety, and support for healthy inflammation response via their interaction with multiple targets which will be discussed in this article. 

Given that hemp contains over 125 cannabinoids, we will focus on CBD, one of the most extensively researched and abundant cannabinoids found in nature.

Molecular Targets of CBD

The molecular targets of CBD are diverse, with its interaction primarily involving receptors, transporters, ion channels, and enzymes. These interactions contribute to CBD’s wide-ranging effects, from modulating pain and inflammation to influencing mood and cognition.

In total, CBD targets more than 65 distinct molecular sites within the body, which can be divided into four key categories:

1. Receptors 
2. Transporters 
3. Ion Channels 
4. Enzymes

Receptor Targets of CBD

Receptors are specialized protein structures that receive and respond to signals from various substances, such as ions, neurotransmitters or hormones. These interactions play a crucial role in regulating various physiological processes.

Research indicates that CBD interacts with more than 10 distinct receptor targets, each contributing to its unique therapeutic effects. The primary receptors affected by CBD include:
–

• Cannabinoid Receptors (CB1 and CB2): These are the most well-known receptors for cannabinoids. CB1 receptors are primarily found in the central nervous system, while CB2 receptors are mainly located in the immune system and peripheral tissues. CBD’s modulating interaction with these receptors can modulate pain, inflammation, and immune responses.
• Adenosine Receptors (A1R & A2R): Adenosine receptors influence various physiological processes, including regulating neuronal activity, sleep, heart rate, and inflammation. By interacting with these receptors, CBD may help improve seizures, sleep patterns, and reduce inflammation.
• Glycine Receptors (GlyR): Glycine receptors play a role in modulating pain, inflammation, and motor functions. CBD’s interaction with α1 and α1β glycine receptors may contribute to its analgesic, neuroprotective, anti-inflammatory, and muscle-relaxing effects.
• Opioid Receptors (ORs): These receptors are involved in pain regulation. CBD’s interaction with mu and delta opioid receptors suggests it may enhance the pain-relieving effects of traditional opioid-based treatments without the risk of dependence.
• Serotonin Receptors (5-HT1): Serotonin plays a critical role in mood, gut motility and secretion, and pain regulation. CBD’s influence on 5-HT1 serotonin receptors may help improve mood, reduce anxiety, chronic pain, IBS symptoms, and enhance overall well-being.
• G Protein-coupled Receptor 55 (GPCR55): This receptor is involved in regulating neuronal activity and is linked to various brain functions. CBD’s interaction with GPCR55 is shown to influence mood, bone cell balance, and potentially modulate pain perception.
• Nicotinic Acetylcholine Receptors (nAchRs): These receptors play a role in muscle control, cognitive function, and the nervous system. CBD’s interaction with nAchRs may help improve memory, cognition, and muscle relaxation, but its exact significance is unclear.
• Peroxisome Proliferator-activated Receptors (PPARγ): PPARγ receptors are involved in regulating metabolic processes, inflammation, and insulin sensitivity. CBD’s action on PPARγ may help reduce inflammation and promote metabolic health.

Enzyme Targets of CBD

Research also shows that CBD interacts with over 32 enzymes, many of which play roles in metabolic processes. Some of these enzyme targets are discussed below:

A. Enzymes Involved in Xenobiotic Metabolism

CBD interacts with various enzymes, influencing metabolic processes and contributing to its therapeutic effects. A number of key enzyme targets and their interactions with CBD include:
–

1. Cytochrome P450 (CYP450) Family: CBD inhibits several CYP450 enzymes, affecting drug metabolism.
   • CYP2C19: CBD acts as a potent inhibitor, potentially altering the metabolism of drugs processed by this enzyme.
   • CYP2C9: CBD inhibits this enzyme, which may influence the breakdown of certain medications.
   • CYP2D6: CBD serves as a potent inhibitor, affecting the metabolism of drugs metabolized by CYP2D6.
   • CYP1A1, CYP1A2, CYP1B1: CBD inhibits these enzymes, which are involved in the metabolism of various xenobiotics.
   • CYP3A4, CYP3A5, CYP3A7: CBD inhibits these enzymes, potentially affecting the metabolism of a wide range of drugs. 
     1. Note that CYP3A4 alone metabolizes about 60% of all prescribed drugs. However, most CBD-drug interactions are not clinically meaningful, except for the anticonvulsant valproate, which may increase liver enzymes.
2. NRF2 (Nuclear Factor Erythroid 2–Related Factor 2): CBD activates NRF2, leading to the upregulation of antioxidant defenses and protection against oxidative stress, cancer, cardiovascular dysfunctions, and neurodegenerative conditions.
   –
3. Antioxidant Enzymes: CBD enhances the activity of enzymes that combat oxidative stress.
   • Catalase: Increased activity helps decompose hydrogen peroxide, reducing oxidative damage.
   • Superoxide Dismutase (SOD): Enhanced activity aids in dismutating superoxide radicals into less harmful molecules.
   • NAD(P)H Quinone Reductase: Amplified activity contributes to the detoxification of quinones and protection against oxidative stress.
   • Glutathione Peroxidase and Glutathione Reductase: Increased activities support the reduction of peroxides and regeneration of glutathione, a vital cellular antioxidant.

B. Enzymes Involved in Cholesterol Metabolism
–

1. Acyl-Cholesterol Acyltransferases (ACATs): CBD inhibits ACATs, potentially reducing cholesterol esterification and influencing cholesterol homeostasis. CBD’s inhibition of ACATs suggests it may play a role in improving health rather than merely maintaining it. By reducing cholesterol esterification, CBD could help regulate cholesterol balance, potentially lowering the risk of plaque buildup in arteries and supporting cardiovascular health.
   –
2. Progesterone 17α-Hydroxylase: CBD may inhibit this enzyme, affecting steroid hormone biosynthesis. This could influence hormone balance, potentially supporting conditions related to estrogen and testosterone regulation, such as hormonal imbalances, polycystic ovary syndrome (PCOS), or adrenal disorders. By modulating steroid hormone levels, CBD may contribute to improved metabolic function, mood stability, and overall endocrine health.
   –
   
3. Testosterone 6α-Hydroxylase and 16β-Hydroxylase: CBD’s interaction with these enzymes could influence testosterone metabolism and related physiological processes.

C. Enzymes Controlling Ceramide Levels
–

1. Sphingomyelinase: CBD stimulates this enzyme, potentially increasing ceramide production. This may improve skin hydration, antibacterial effects, and influence other cell signaling pathways related to apoptosis (cell death) and inflammation.

D. Electron Transport Chain Enzymes

CBD interacts with key components of the mitochondrial electron transport chain, which plays a crucial role in cellular energy production:

• • • ETC Complex I
    • ETC Complex II
    • ETC Complex III
    • ETC Complex IV

E. Other Enzymes

CBD also affects various enzymes involved in neurotransmitter regulation, inflammation, and lipid metabolism:
–

• • • Arylalkylamine N-Acetyltransferase (AANAT) – Regulates melatonin synthesis and circadian rhythms.
    • Phospholipase A2 (PLA2) – Involved in inflammatory pathways by releasing arachidonic acid.
    • Fatty Acid Amide Hydrolase (FAAH) – Breaks down anandamide, influencing pain and mood regulation.
    • Cyclooxygenase-1 (COX-1) & Cyclooxygenase-2 (COX-2) – Mediate inflammation and pain response.
    • 15-Lipoxygenase (15-LOX) & 5-Lipoxygenase (5-LOX) – Contribute to inflammatory and oxidative stress pathways.
    • Indoleamine 2,3-Dioxygenase (IDO) – Plays a role in immune regulation and tryptophan metabolism.

Ion Channel and Transporter Targets of CBD

CBD also interacts with more than 10 ion channels and 13 transporter targets, which are responsible for maintaining cellular functions like neurotransmitter release and ionic balance. CBD’s effects on TRP channels, including TRPV1, TRPV2, and TRPM8, may explain its ability to influence pain perception, temperature regulation, and other sensory processes.

Moreover, CBD interacts with various neurotransmitter transporters, including those for dopamine, glutamate, and GABA. By modulating the uptake of these neurotransmitters, CBD may help regulate mood and anxiety, and result in improved cognitive function.

Conclusion

The interaction between cannabinoids and their molecular targets happens simultaneously and can be influenced by other compounds, including cannabinoids, terpenes, and flavonoids. For example, flavonoids are shown to modulate the CYP450 enzymes, which play a key role in metabolizing CBD. This will ultimately reduce the level at which CBD is broken down by our body, thereby providing a more lasting effect. Meanwhile, terpenes may enhance CBD’s ability to interact with these receptors. 

The benefits of this synergy are lost when using isolates. That’s why BioSource Botanicals is committed to our Active-Spectrum Extracts™, which preserve all naturally occurring cannabinoids, terpenes, and even flavonoids found in the hemp plant. By maintaining these compounds, our extracts enhance the activation of multiple molecular targets, delivering faster and more effective relief—even at lower doses.

References
–

1. Ahrens, J., Demir, R., Leuwer, M., de la Roche, J., Krampfl, K., Foadi, N., Karst, M., & Haeseler, G. (2009). The Nonpsychotropic Cannabinoid Cannabidiol Modulates and Directly Activates Alpha-1 and Alpha-1-Beta Glycine Receptor Function. Pharmacology, 83(4), 217–222. https://doi.org/10.1159/000201556
2. Brown, K., Funk, K., Figueroa Barrientos, A., Bailey, A., Shrader, S., Feng, W., McClain, C. J., & Song, Z.-H. (2024). The Modulatory Effects and Therapeutic Potential of Cannabidiol in the Gut. Cells, 13(19), 1618. https://doi.org/10.3390/cells13191618
3. Ferreira, B. P., Costa, G., Mascarenhas-Melo, F., Pires, P. C., Heidarizadeh, F., Giram, P. S., Mazzola, P. G., Cabral, C., Veiga, F., & Paiva-Santos, A. C. (2023). Skin applications of cannabidiol: Sources, effects, delivery systems, marketed formulations and safety. Phytochemistry Reviews, 22(3), 781–828. https://doi.org/10.1007/s11101-023-09860-5
4. Ibeas Bih, C., Chen, T., Nunn, A. V. W., Bazelot, M., Dallas, M., & Whalley, B. J. (2015). Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics, 12(4), 699–730. https://doi.org/10.1007/s13311-015-0377-3
5. Iffland, K., & Grotenhermen, F. (2017). An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis and Cannabinoid Research, 2(1), 139–154. https://doi.org/10.1089/can.2016.0034
6. Jiang, R., Yamaori, S., Takeda, S., Yamamoto, I., & Watanabe, K. (2011). Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sciences, 89(5), 165–170. https://doi.org/10.1016/j.lfs.2011.05.018
7. Kathmann, M., Flau, K., Redmer, A., Tränkle, C., & Schlicker, E. (2006). Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 372(5), 354–361. https://doi.org/10.1007/s00210-006-0033-x
8. Li, X., Yennawar, M., Wiest, A., O’Brien, W. T., Babrowicz, B., White, R. S., Talos, D. M., & Jensen, F. E. (2024). Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice. European Journal of Neuroscience, 59(12), 3337–3352. https://doi.org/10.1111/ejn.16350
9. Maayah, Z. H., Takahara, S., Ferdaoussi, M., & Dyck, J. R. B. (2020). The molecular mechanisms that underpin the biological benefits of full-spectrum cannabis extract in the treatment of neuropathic pain and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1866(7), 165771. https://doi.org/10.1016/j.bbadis.2020.165771
10. Mahgoub, M., Keun-Hang, S. Y., Sydorenko, V., Ashoor, A., Kabbani, N., Al Kury, L., Sadek, B., Howarth, C. F., Isaev, D., Galadari, S., & Oz, M. (2013). Effects of cannabidiol on the function of α7-nicotinic acetylcholine receptors. European Journal of Pharmacology, 720(1), 310–319. https://doi.org/10.1016/j.ejphar.2013.10.011
11. Millar, S. A., Stone, N. L., Yates, A. S., & O’Sullivan, S. E. (2018). A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Frontiers in Pharmacology, 9, 1365. https://doi.org/10.3389/fphar.2018.01365
12. Moon, Y. J., Wang, X., & Morris, M. E. (2006). Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism. Toxicology in Vitro, 20(2), 187–210. https://doi.org/10.1016/j.tiv.2005.06.048
13. Radwan, M. M., Chandra, S., Gul, S., & ElSohly, M. A. (2021). Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis. Molecules, 26(9), 2774. https://doi.org/10.3390/molecules26092774
14. Ramer, R., Heinemann, K., Merkord, J., Rohde, H., Salamon, A., Linnebacher, M., & Hinz, B. (2013). COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells. Molecular Cancer Therapeutics, 12(1), 69–82. https://doi.org/10.1158/1535-7163.MCT-12-0335
15. Russo, E. B., Burnett, A., Hall, B., & Parker, K. K. (2005). Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochemical Research, 30(8), 1037–1043. https://doi.org/10.1007/s11064-005-6978-1
16. Silvestro, S., Mammana, S., Cavalli, E., Bramanti, P., & Mazzon, E. (2019). Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials. Molecules, 24(8), 1459. https://doi.org/10.3390/molecules24081459
17. Talebi, M., Sadoughi, M. M., Ayatollahi, S. A., Ainy, E., Kiani, R., Zali, A., & Miri, M. (2023). Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway. Biomedicine & Pharmacotherapy, 168, 115805. https://doi.org/10.1016/j.biopha.2023.115805
18. Usami, N., Yamamoto, I., & Watanabe, K. (2008). Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone. Life Sciences, 83(21), 717–724. https://doi.org/10.1016/j.lfs.2008.09.011
19. Vučković, S., Srebro, D., Vujović, K. S., Vučetić, Č., & Prostran, M. (2018). Cannabinoids and Pain: New Insights From Old Molecules. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.01259
20. Whyte, L. S., Ryberg, E., Sims, N. A., Ridge, S. A., Mackie, K., Greasley, P. J., Ross, R. A., & Rogers, M. J. (2009). The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proceedings of the National Academy of Sciences, 106(38), 16511–16516. https://doi.org/10.1073/pnas.0902743106