Effects on Non-Endocannabinoid Signaling Systems

Does CBD bind to the receptors of and modulate the activities of any non-endocannabinoid signaling systems?

Yes, CBD binds and interacts with several non-endocannabinoid signaling systems. However, it is not clear if any of these interactions are responsible for CBD’s effects. Below is a list of many of the non-endocannabinoid receptor systems with which CBD interacts.

• Serotonin 5-HT1A: CBD is a partial agonist of the serotonin 5-HT1A receptor. (Bisogno, Campos 2017, Campos 2008, Thomas, Brown) Agonist activities on 5-HT1A receptors are involved with anti-craving effects, regulating the drug reward system, anxiety symptoms, improving stress management (Prud’Homme), and anti-inflammatory/immunomodulatory pathways. (Balachandran) Activation of the 5-HT1A  receptor system  also leads to  antipsychotic, anticonvulsant, antioxidant, and analgesic effects. (Balachandran)
• Adenosine A2_A: CBD is an agonist of the adenosine A2_A receptor (Urits) and CBD also inhibits adenosine uptake. (WHO 39 p 13, Calapai, Carrier, Ross) The A2_A receptor system is associated with anti-inflammatory pathways. (Urits, Nichols)
• μ- and δ-opioid receptors: CBD is an allosteric modulator of the μ- and δ-opioid receptors. (Calapai, Kathmann, Brown) The μ- and δ-opioid receptors modulate pain pathways.
• Peroxisome proliferator-activated gamma receptor  CBD is an agonist of the peroxisome proliferator-activated gamma receptor (PPARγ). (Calapai) The PPARγ receptor system is associated with anti-inflammatory pathways. (Urits, Nichols)
• TRPV1: CBD is an agonist of the transient receptor potential vanilloid ion channel TRPV1 – the same receptor at which capsaicin acts. (WHO-39 p 7, Bonaccorso, Bisogno, Boggs, Campos 2017; Campos 2008, Thomas, Brown, Breijyeh) Agonist activity at the TRPV1 receptor results in anxiolytic, antipsychotic, anticonvulsant, antioxidant, analgesic, and immunomodulatory processes. (Balachandran)
• Glycine receptor system: CBD is an enhancer of activity at glycine receptor subtypes. (WHO 39, p13) The glycine receptor system is involved in motor control and pain perception. (Avila)
• GPR55: CBD is reported to function as a GPR55 antagonist and suppress GPR55’s activities. (WHO 39 p 13, Boggs) The GPR55 receptor system is associated with psychotic and epileptic activities. (Sylantyev)
• Equilibrative nucleoside transporter (ENT): CBD is a blocker of the equilibrative nucleoside transporter (ENT). (Carrier)
• TRPM8: CBD is a blocker of the transient receptor potential of melastatin type 8 (TRPM8) channel. (Ferreira, Lim) The TRPM8 receptor system is involved with immunomodulation and inflammatory pathways, along with many other pathways. (Khalil)
• TRPA1 and TRPV4: CBD is an activator of TRPA1 and TRPV4 cation channels. (Page)
• Dopamine transporter: CBD is an inhibitor of the dopamine uptake transporter. (Ferreira) Inhibition of dopamine uptake leads to increases in the endogenous levels of dopamine. (Ferreira) Also, in mice, CBD acts as a negative allosteric modulator of dopamine D2 receptors, suggesting that CBD can modulate the dopaminergic neurotransmission in basal ganglia. (Brown, Ferreira)

Note: It must be pointed out that many of the above listed effects “only manifest at high concentrations, which may be difficult to achieve in vivo.” (Calapai)

References

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• Campos AC, Fogaça MV, Scarante FF, Joca SRL, Sales, AJ, Gomes FV, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 2017; 23 (8):269.
• Campos AC, Guimarães F.S., Involvement of 5HT1A receptors in the anxiolytic- like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 2008; 199(2):223–230.
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