CBD

The main cannabinoid receptor in the brain, responsible for THC’s intoxicating effects, binds CBD negligible. One established assay reported a CB1 Ki of 4,350 nM, compared with about 40.7 nM for Delta-9-THC, making Delta-9-THC roughly 107x stronger in binding affinity under those conditions.

Rather than activating CB1, CBD acts as a negative allosteric modulator, binding at a different site on the receptor and reducing the activity of CB1 agonists such as THC. This weakens some CB1-related effects instead of producing THC-like intoxication itself.

The main cannabinoid receptor in the immune system, involved in regulating immune cell activity and inflammatory responses. CBD binds CB2 relatively weakly, with a reported Ki of approximately 2,860 nM, compared with 36.4 nM for Delta-9-THC, making its direct binding around 79x weaker.

CBD’s functional activity at CB2 is complex and depends on the signalling pathway studied. Research has identified CBD as a CB2 inverse agonist in some experiments, while other studies have found agonist-like activity. CBD can therefore modify CB2 signalling despite its weak direct binding, but it should not be described as a direct CB2 agonist.

The likely source of the confusion is that many of CBD’s anti-inflammatory effects are associated with CB2-related immune pathways, but that does not mean CBD strongly binds to and directly activates CB2.

Voltage-gated sodium channels help control how easily nerve cells become activated and send repeated electrical signals. CBD inhibits several of these channels, including NaV1.7, and can stabilise them in an inactive state. Research found that 300 nM CBD reduced NaV1.7 activity by about 71% under the tested conditions. This could help reduce overactive nerve-cell activity and may contribute to CBD’s effects on seizures and pain.

TRP channels help sensory nerve cells detect signals such as heat, cold, irritation and pain. CBD interacts with several of these channels and can change how strongly they respond to stimulation.

CBD activates TRPA1 at about 0.11 µM, TRPV1 at 1.0 µM and TRPV2 at 1.25 µM. After this initial activation, the channels can become desensitised, meaning they respond less strongly to further stimulation. This may help reduce pain-related and irritation-related signalling after the initial activation.

CBD also blocks the cold-sensitive TRPM8 channel, with an IC50 of approximately 0.06 µM. Together, these actions suggest that TRP channels may contribute to CBD’s effects on pain perception, sensitivity to temperature and inflammatory responses, although their exact importance in humans is still uncertain.

T-type calcium channels help control how easily nerve cells become activated and are involved in pain signalling, sleep and seizure-related brain activity. CBD inhibits the human CaV3.1, CaV3.2 and CaV3.3 channels, reducing their activity by roughly 40 to 55% at 1 µM in laboratory experiments.

Animal research also directly linked CaV3.2 inhibition to CBD’s pain-reducing effects. This suggests that T-type calcium channel inhibition may be an important mechanism behind some of CBD’s effects on pain, although its importance in humans remains uncertain.

Adenosine is a natural signalling molecule involved in inflammation, nerve activity and responses to tissue stress. CBD inhibits the ENT1 transporter, which normally helps move adenosine back into cells. CBD allows more adenosine to remain available outside cells for longer, which can strengthen the effects of adenosine in the body.

Animal and laboratory research found that this mechanism can reduce inflammatory responses, particularly through A2A receptors. Newer research also suggests that CBD can directly modify A2A receptor activity, reducing how strongly the receptor responds when activated. CBD may therefore influence adenosine signalling both by increasing available adenosine and by changing A2A receptor responses, but the exact effects and their importance in humans remains uncertain.

Glycine receptors help reduce nerve-cell activity and are involved in controlling pain signalling. CBD acts as a positive allosteric modulator, meaning it strengthens the normal effects of glycine at these receptors. An EC50 of approximately 12.3 µM has been measured at α1 glycine receptors.

Animal research also linked CBD’s activity at α3 glycine receptors to reduced inflammatory and neuropathic pain, although the importance of this mechanism in humans remains uncertain.

The 5-HT1A serotonin receptor helps regulate mood, stress responses and serotonin signalling. CBD has shown modest agonist activity at human 5-HT1A receptors, although direct activation required relatively high concentrations, around 16 µM in the original study. Preclinical evidence links this receptor to some behavioural effects of CBD, but its contribution in humans is not fully established.

GPR55 helps regulate calcium signalling and communication between nerve cells. CBD acts as a GPR55 antagonist, meaning it can reduce activity triggered through this receptor. This could potentially help calm overactive brain signalling, although its importance for CBD’s effects in humans is still being studied.

CBD is extensively metabolised by liver enzymes. The major pathway produces 7-OH-CBD, a pharmacologically active metabolite, followed by 7-COOH-CBD, which reaches substantially higher concentrations in human blood. CBD and its metabolites can also affect CYP enzyme activity, creating clinically documented drug interactions.