Cannabis has been used for thousands of years as a medicine (see History for further details), but the active ingredients in the plant and the biological targets in the body were discovered only decades ago.
The most abundant pharmacological ingredients in cannabis, THC and CBD, are phytocannabinoids (which means that they are cannabinoids originating from a plant) and were identified in the 1960s. The search for the physiological binding site of the euphoric THC led to the discovery of two new receptors in the early 1990s; these were therefore named ‘cannabinoid receptors’ (CB1 and CB2). The body’s own binding partners for these receptors were accordingly named ‘endocannabinoids’, as they are endogenous cannabinoids, i.e. they originate within the body. Together with the enzymes involved in the synthesis and breakdown of endocannabinoids, these components form the Endocannabinoid System (ECS)1,2.
Conserved down through evolution, the ECS is an essential physiological system in humans and animals alike. It helps maintain the balance of a variety of important bodily functions – such as appetite, energy, pain perception, mood, memory, temperature, immune responses and more3. This might explain why cannabis is used for such a broad range of symptoms.
The two main receptors in the ECS (CB1 and CB2) are both G-protein-coupled receptors that initiate signal cascades when activated but they have different tissue distributions and functions. Both receptors are widely expressed throughout the body, but CB1 is highly abundant in the central nervous system (CNS), whereas CB2 is highly present in immune cells. The number of CB2 receptors increases upon tissue injury or inflammation2,4.
Distribution of endocannabinoid receptors (CB1 and CB2) in the body.
The endocannabinoids discovered first and described in the greatest detail are anandamide (AEA, Ananda is the Sanskrit word for ‘bliss’) and 2-arachidonoylglycerol (2-AG). AEA binds and activates CB1 more strongly than CB2, whereas 2-AG binds and activates both receptors equally. The endocannabinoids are metabolised by the enzymes FAAH (AEA) and MAGL (2-AG)1,4.
The main phytocannabinoids, THC and CBD, bind differently to CB1 and CB2. THC binds and activates both CB1 and CB2, whereas CBD only binds very weakly to the conventional (orthosteric) binding sites of CB1 and CB2. Instead, CBD binds more strongly to another (allosteric, i.e. modulating) binding site on CB1, which can affect its binding affinity to other molecules including the endocannabinoids and THC5. Apart from CB1 and CB2, endocannabinoids and phytocannabinoids both induce pharmacological effects by interacting with various other targets. For more details, see our reference list below for articles on this topic3,4,6.
Interaction of cannabinoids with the endocannabinoid receptors (CB1 and CB2).
In addition to the main cannabinoids THC and CBD, it has also been suggested that other compounds from the plants – such as the minor cannabinoids, terpenes and flavonoids – could have beneficial therapeutic effects and potentially influence the effect of each other when combined. This is referred to as the ‘entourage effect’7. The mechanism of action for all the minor secondary compounds in the plant is poorly investigated, however, and more research is needed to truly clarify this topic.
1. Howlett, A. C. & Abood, M. E. CB1 and CB2 Receptor Pharmacology. Advances in Pharmacology 80, 169–206 (2017).
2. Zou, S. & Kumar, U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International journal of molecular sciences 19, (2018).
3. Lowe, H. et al. The endocannabinoid system: A potential target for the treatment of various diseases. International Journal of Molecular Sciences vol. 22 (2021).
4. Lu, H. C. & MacKie, K. An introduction to the endogenous cannabinoid system. Biological Psychiatry vol. 79 516–525 (2016).
5. Zagzoog, A. et al. In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa. Scientific Reports 10, (2020).
6. Morales, P., Hurst, D. P. & Reggio, P. H. Molecular Targets of the Phytocannabinoids-A Complex Picture. Progress in the chemistry of organic natural products 103, 103 (2017).
7. Russo, E. B. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology vol. 163 1344–1364 (2011).