What pharmacologic effects do the non‑tetrahydrocannabinol (non‑THC) constituents of cannabis, such as cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and terpenes, have?

Pharmacologic Effects of Non-THC Cannabis Constituents

The non-THC components of cannabis—including cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and terpenes—interact with multiple receptor systems beyond the classic cannabinoid receptors, producing diverse pharmacological effects including modulation of pain pathways, inflammation, and neurological function, though clinical evidence for most therapeutic applications remains insufficient. 1

Cannabidiol (CBD)

Mechanism of Action

• CBD does not act as an agonist at CB1 or CB2 receptors; instead, it functions as a negative allosteric modulator of cannabinoid receptors and has been shown to reduce adverse effects of THC in human studies 2
• CBD increases endocannabinoid signaling through multiple pathways: enhancing serotonin receptor 1A activity, promoting adenosine signaling, and activating TRPV1 receptors that detect thermal and nociceptive stimuli 2
• CBD potently activates and desensitizes rat TRPA1 channels and is the only cannabinoid tested that inhibits fatty acid amide hydrolase (FAAH), an enzyme that breaks down endocannabinoids 3

Clinical Effects and Safety

• CBD at doses of 300 mg or more per day carries risk for reversible liver enzyme abnormalities, with a nearly 6-fold increase in liver enzyme elevation and drug-induced liver injury reported primarily in epilepsy populations 1
• No cases of hepatotoxicity occurred at CBD doses below 300 mg/day 1
• CBD is free of THC's neuropsychiatric liabilities (euphoria, paranoia, psychosis) but monitoring liver enzymes may be important in cancer and other clinical settings 1
• CBD inhibits multiple cytochrome P450 enzymes (CYP3A4, UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19), creating potential for drug-drug interactions 1

Cannabigerol (CBG)

Receptor Activity

• CBG is a partial agonist at both CB1 and CB2 receptors and acts as a regulator of endocannabinoid signaling 4
• CBG potently activates and desensitizes rat TRPV2 channels and stimulates human TRPV1 receptors 3, 5
• CBG-containing botanical extracts are among the most potent TRPM8 antagonists tested 3

Pharmacological Targets

• CBG targets include TRP channels, COX-1 and COX-2 enzymes, and 5-HT1A and alpha-2 receptors 4
• CBG inhibits anandamide cellular uptake and certain botanical extracts inhibit N-acylethanolamine acid amide hydrolase (NAAA) 3
• CBG is metabolized in the liver by CYP2J2 to produce hydroxyl and di-oxygenated products 4

Reported Effects

• Pre-clinical findings suggest CBG possesses antioxidant, anti-inflammatory, anti-tumoral, anti-anxiety, neuroprotective, and appetite-stimulating effects, though clinical evidence remains limited 4
• CBG use among US adults is relatively low (1.3% lifetime prevalence), with most users citing medical rather than recreational purposes 6

Cannabichromene (CBC)

Receptor Interactions

• CBC is a potent rat TRPA1 agonist and desensitizer, along with CBD and CBN 3
• CBC potently activates and desensitizes rat TRPV2 channels 3
• CBC shows the weakest CB1 receptor binding affinity among tested cannabinoids but still demonstrates measurable binding 7, 3

Metabolic Effects

• CBC inhibits anandamide cellular uptake more potently than other cannabinoids tested 3
• CBC-containing botanical extracts inhibit NAAA, an enzyme involved in endocannabinoid metabolism 3

Therapeutic Potential

• CBC has been suggested to have anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects, though most evidence comes from preliminary studies 8
• CBC did not produce THC-like discriminative stimulus effects in mice, suggesting it lacks psychoactive properties similar to THC 7

Cannabinol (CBN)

Pharmacological Activity

• CBN is a potent rat TRPA1 agonist but does not activate TRPV2 channels like other cannabinoids 3
• CBN partially substituted for THC in drug discrimination studies, suggesting some cannabimimetic subjective effects, though less than THC itself 7
• CBN inhibits anandamide cellular uptake 3

Clinical Use Patterns

• CBN lifetime use among US adults is 4.5%, with most users (majority) citing medical rather than recreational purposes 6
• The most common medical reasons for CBN use are insomnia (15.4%), pain (11.1%), and anxiety (10.9%) 6

Terpenes (β-Caryophyllene)

Receptor Activity

• β-caryophyllene (BC) and β-caryophyllene oxide (BCO) exhibit negligible affinity for both CB1 and CB2 receptors 7
• BCO did not alter the discriminative stimulus effects of THC in animal models 7
• Terpenes contribute to the "entourage effect" through complicated synergistic and inhibitory interactions with cannabinoids, though this phenomenon is not fully characterized 1

Critical Clinical Considerations

Drug Interactions

• Cannabis constituents inhibit cytochrome P450 enzymes, potentially increasing toxicity or decreasing potency of chemotherapeutics and other medications 1
• Drug interactions with warfarin are classified as very high risk, while buprenorphine and tacrolimus are high risk 1
• Clinical data on drug-drug interactions remain scant, limiting clinicians' ability to provide informed guidance 1

Evidence Limitations

• The certainty of evidence for most cannabinoid outcomes is low or very low 1
• Cannabis and cannabinoid access has outpaced the science supporting clinical use 1
• Scientific evidence for THC's biological impacts may not fully capture the effects of whole-plant cannabis due to the entourage effect 1

Absorption and Formulation

• Nanoemulsion formulations significantly increase portal vein absorption (11-fold for CBD, 71-fold for CBG, 8-fold for CBC, 13-fold for CBN) compared to oil solutions 9
• Intestinal lymphatic transport plays a major role in absorption of CBD, CBG, CBC, and CBN 9
• Planarity of the molecule and low surface polarity facilitate lymphatic transport 9