Pharmacology, mechanisms of action, clinical effects, pharmacokinetics and safety considerations for the four main cannabinoids — written for prescribers, pharmacists and healthcare professionals advising patients on cannabis-based medicines.
Cannabis sativa contains over 100 identified cannabinoids, of which four — THC, CBD, CBG and CBN — are clinically most relevant for healthcare professionals working with cannabis-based medicines. This publication provides a structured pharmacological overview of each cannabinoid, focused on the information most relevant to clinical practice.
This publication is for healthcare professional education. It does not constitute prescribing guidance. Clinical decisions should be based on individual patient assessment and current national guidelines.
The endocannabinoid system (ECS) is a lipid-based retrograde signalling system that regulates multiple physiological processes including pain modulation, inflammation, mood, memory, appetite and sleep. The ECS consists of endogenous cannabinoids (endocannabinoids — primarily anandamide and 2-AG), cannabinoid receptors (primarily CB1 and CB2) and enzymes responsible for endocannabinoid synthesis and degradation.
CB1 receptors are predominantly expressed in the central nervous system — particularly in brain regions involved in pain processing, memory, emotion and motor control. CB2 receptors are predominantly expressed in immune cells and peripheral tissues. Phytocannabinoids (plant-derived cannabinoids) interact with this system, primarily through CB1 and CB2 receptor agonism or antagonism, but also through non-receptor mechanisms.
THC is the primary psychoactive cannabinoid in cannabis. It acts as a partial agonist at CB1 and CB2 receptors. CB1 agonism in the CNS produces the well-known psychoactive effects — euphoria, relaxation, altered perception, cognitive impairment — as well as the therapeutic effects including analgesia, anti-nausea and appetite stimulation.
Oral bioavailability: 4–20% (highly variable; first-pass metabolism). Onset: 1–3 hours. Duration: 4–8 hours. Inhalation bioavailability: 10–35%. Onset: minutes. Duration: 2–4 hours. THC is highly lipophilic; distributes extensively to adipose tissue; metabolised by CYP2C9 and CYP3A4 to active metabolite 11-OH-THC and inactive 11-nor-9-carboxy-THC.
Dose-dependent: tachycardia, anxiety, paranoia, dizziness, cognitive impairment, sedation. Acute psychosis at high doses, particularly in predisposed individuals. Cannabis use disorder with chronic use — approximately 9% of all users; higher with early-onset or high-frequency use.
CBD is non-psychoactive and has complex pharmacology involving multiple receptor systems. It is a negative allosteric modulator of CB1 — it does not activate CB1 directly but modulates THC's CB1 effects, potentially reducing psychoactive adverse effects. CBD also acts on serotonin (5-HT1A), TRPV1, GPR55, adenosine A2A and multiple other receptor systems.
Oral bioavailability: 6–19% (substantially increased by high-fat meal). Onset: 1–6 hours. Duration: 6–12 hours. CBD is metabolised primarily by CYP3A4 and CYP2C19. Important drug interaction: CBD inhibits CYP2C19 and is a time-dependent inhibitor of CYP3A4 — interactions with clobazam, warfarin, tacrolimus and other CYP-metabolised drugs are documented and clinically significant.
Generally well tolerated. Diarrhoea, nausea, fatigue and elevated liver enzymes (hepatotoxicity) at high doses. Hepatotoxicity risk increased with concomitant valproate use. Unlike THC, CBD does not cause psychoactive effects and has low abuse potential.
CBG is a non-psychoactive cannabinoid often referred to as the "precursor cannabinoid" because CBGA (the acid form) is the biochemical precursor to THC, CBD and CBC. CBG acts as a partial agonist at CB1 and CB2, with some alpha-2 adrenoceptor agonism and 5-HT1A antagonism.
Clinical evidence for CBG is limited — robust RCTs are lacking. Preclinical evidence suggests potential in inflammatory bowel disease, glaucoma, neuroprotection and antibacterial applications. CBG is present in low concentrations in most cannabis varieties; some cultivars are selectively bred for higher CBG content.
CBG is currently of limited direct clinical relevance due to the absence of RCT evidence. Healthcare professionals should be aware that patients may seek CBG-containing products based on preclinical data or commercial claims that exceed the evidence base.
CBN is formed by the oxidative degradation of THC. It is present in very low concentrations in fresh cannabis but accumulates over time as THC degrades, particularly with light and heat exposure. CBN is a weak partial agonist at CB1 and CB2 — approximately 10% of THC's potency at CB1.
Clinical evidence for CBN is minimal. CBN has been marketed as a sleep aid based largely on anecdotal reports and early (methodologically limited) human data. A 2023 trial found CBN did not outperform placebo for subjective sleep quality in healthy adults. Other marketed benefits — analgesic, anti-inflammatory, appetite stimulant — are based on preclinical data only.
CBN is clinically significant as a stability-indicating marker. Elevated CBN content in a cannabis product indicates degradation of THC — due to improper storage, excessive age or manufacturing process failures. A product with significantly elevated CBN may have reduced potency. Specifications for THC-dominant cannabis products should include a CBN limit as a stability parameter.
| Property | THC | CBD | CBG | CBN |
|---|---|---|---|---|
| Psychoactive | Yes | No | No | Mildly (weak) |
| CB1 activity | Partial agonist | Negative allosteric modulator | Partial agonist (weak) | Partial agonist (weak) |
| Strongest clinical evidence | Pain, CINV, spasticity | Refractory epilepsy | Limited | Limited |
| Abuse potential | Yes | Low | Unknown | Unknown |
| Key drug interaction risk | CYP2C9, CYP3A4 | CYP2C19, CYP3A4 | Unknown | Unknown |
| Clinical maturity | Established | Established (epilepsy) | Preclinical | Preclinical |
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