Diversity of Molecular Targets and Signalling Pathways for CBD

Diversity of Molecular Targets and Signalling Pathways for CBD

Cannabis has been used both recreationally and medicinally for thousands of years, yet the mechanisms through which cannabis compounds affect the human body remain relatively unclear. Many studies have indicated that cannabis may be helpful in the treatment of various medical conditions and illnesses.

Cannabidiol – known commonly as CBD – is one of the most common cannabinoids produced by the cannabis plant. Alongside tetrahydrocannabinol (THC), this compound has gained interest for its medicinal and therapeutic potential. However, unlike THC, CBD does not have euphoria eliciting properties when consumed in high quantities.  

CBD is increasingly investigated in the development of new medications for various conditions including epilepsy, PTSD, anxiety and depression, and chronic pain. Therefore, it is essential to understand the molecular targets and signalling pathways for CBD. A recent review assessed the current evidence on the molecular targeting of CBD and the pathways through which it works.

What are the Effects of CBD?

CBD has been found to alter a number of physiological functions and neuronal activity. The phyto-cannabinoid has demonstrated potential as an anti-inflammatory agent, and an ability to improve motor activity and various symptoms of depression and anxiety, as well as playing a role in both Type 1 and Type 2 diabetes.

Various studies have also found that CBD may have the potential to reduce anxiety and psychosis. Similarly, it has also be proposed to reduce the incidence of side effects of THC when co-administered.

A number of studies have found that CBD can reverse, or limit, anxiety states seen after the administration of THC. This could be a result of CBD’s negative allosteric modulation of CB1 receptors. It has also been demonstrated to counteract the effects of THC as the ventral hippocampus, an area of the brain heavily associated with emotional processing, such as anxiety.

Molecular Targets and Signalling Pathways

CBD is known to interact with the human endocannabinoid system as an antagonist of both the CB1 and CB2 receptors. However, some of the effects of CBD may be due to the compound’s interaction with other targets, such as the FAAH enzyme. CBD inhibits FAHH which is normally responsible for endocannabinoid degradation. This leads to an increase in endocannabinoid levels and, in turn, receptor activation.

In particular, CBD has been shown to inhibit the breakdown of anandamide through inhibition of FAAH enzymes. Anandamide is the main endogenous CB1 receptor agonist. This may suggest an indirect effect of CBD on cannabinoid receptors through increasing endogenous anadamide.

CBD and GPR55 Receptors

While CB1 and CB2 are considered to be the main cannabinoid receptors, GPR55 is also often proposed to be a third cannabinoid receptor and is implicated in some cannabinoid interactions that do not appear to involve CB1 and CB2.

Some studies suggest that CBD may also function as a GPR55 antagonist. The administration of CBD has been found to decrease the potency of GPR55 agonist CP55940. In one study, the administration of a synthetic regioisomer of CBD, known as abnormal cannabidiol, was found to produce vasodilator effects and reduce blood pressure without any psychotomimetic effects.

CBD and Serotonin Receptors

Serotonin receptor 5-HT1A is proposed to be one of the main molecular targets for CBD. Research has suggested that CBD produces a dose-dependent displacement of binding between 5-HT1A and other agonists. As a 5-HT1A agonist, studies have found that the interaction between CBD and 5-HT1A receptors could play a role in both the anxiolytic and antidepressant effects of CBD administration.

In addition, another study found that CBD was able to attenuate mechanical allodynia (pain). This effect was blocked by selective 5‐HT1a receptor antagonists, but not by selective CB1 and CB2 receptor antagonists, suggesting that CBD interaction with 5-HT1A was responsible for this effect.

CBD and Opioid Receptors

Research by Kathmann et al shows that both THC and CBD act as negative allosteric modulators of opioid receptors as they were seen to accelerate the dissociation and reduce binding of agonists of these receptors. Some researchers have speculated that the interaction between CBD and opioid receptors could play a role in reducing the driving factors behind alcohol seeking behaviour in animal models and subsequently be effective in alcohol and opioid misuse disorders. Clinical data, however, is still awaited to support this.

CBD and Other Potential Molecular Targets

Cannabidiol has been implicated in many other signalling pathways and could potentially have many more molecular targets. Some research, for example, demonstrates that CBD may also affect dopamine signalling in the brain, though not through direct interaction with dopamine receptors.

Various studies have focused on the effects of interactions between CBD and TRPV1 and 5HT1A receptors. Ultimately, the literature shows that CBD has modulating effects at different doses and routes of administration that are largely dependent on its agonistic activity at these receptors. Further research in both pre-clinical and clinical fields is ultimately necessary to further identify the true therapeutic potential of CBD.