THC and CBD: Similarities and differences between siblings

Abstract

Δ⁹-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in their mechanisms of action and effects on brain functions. Both THC and CBD exhibit promising therapeutic properties; however, impairments and increased incidence of mental health diseases are associated with acute and chronic THC use, respectively, and significant side effects are associated with chronic use of high-dose CBD. This review covers recent molecular and preclinical discoveries concerning the distinct mechanisms of action and bioactivities of THC and CBD and their impact on human behavior and diseases. These discoveries provide a foundation for the development of cannabinoid-based therapeutics for multiple devastating diseases and to assure their safe use in the growing legal market of Cannabis-based products.

Figure 1:. Cannabinoid compounds.

A] Cannabis plant. B] Phytocannabinoids THC and CBD (green) produced by the plant, C] THC metabolites 11-OH-THC and THC-COOH (blue) produced by P450 enzymes expressed in liver and brain and D] artificial cannabinoids, CP55940 and JWH-018 (active ingredient in the illegal market product, “Spice”) (red).

Figure 2:. THC metabolism, PK, bioactivity and regiments.

A] Model examples of the PK profiles of THC when inhaled (lungs) or consumed (oral). Examples of resulting behavioral responses associated with low dose THC producing the “high”/euphoria (green arrow), higher dose THC that impairs behavior such as reaction time and judgment (blue arrow), and even higher dose THC (red arrow) that might lead to Cannabis Use Disorder in vulnerable populations, and can be toxic and associated with physiological and psychological panic attack (commonly referred to as “to green-out”; symptoms include sweating, nausea, heart palpitations, hypervigilance, paranoia, and the fear or feeling that you might be dying or about to die). B] Model examples of the PK profile of THC when used to treat pain during the day using several administrations (red line) or to fall asleep with one administration (blue line). A] THC is either metabolized by CYP2C9 that produces 11-OH-THC, which is then metabolized by microsomal alcohol dehydrogenase, or CYP3A4 that produces 8-OH-THC. Conjugation represents the next metabolic step.

Figure 3:. THC inactivation by CYP2C and biased signaling at CB₁R.

A] THC is metabolized to 11-OH-THC by the P450 enzyme CYP2C9. Fatty acid binding proteins (FABP) assist THC in being metabolized. B] THC activates CB₁R that couple to Gα_i proteins that inhibit adenylyl cyclase, Gbg proteins that regulate ion channels and b-arrestin that regulates kinase signaling. Different agonist will often preferentially modulate one of these signaling pathway. FABPassist THC in activating CB₁R.

Figure 4:. Molecular targets modulated by THC.

A] THC modulates CB₁R and CB₂R that are endogenously activated by 2-AG and AEA, and GLRA3 receptors that are endogenously activated by glycine, as demonstrated by in vivo genetic and antagonist experiments. B] THC modulates GPR55 that is endogenously activated by lysophosphatidyl inositol (LPI) and 5-HT3A receptors that are endogenously activated by serotonin, as suggested by cell culture experiments.

Figure 5:. Endocannabinoid signaling.

A] Focus on a synapse between two neurons with adjacent a microglia and an astrocyte (tripartite synapse). B] Presynaptic release of neurotransmitters (gray dotted arrows) stimulates post-synaptic receptors and activate lipases involved in eCB production (light green arrow). Released eCB activate presynaptic CB₁R and inhibit neurotransmitter release (red line), CB₁R expressed by astrocytes and regulate their energy metabolism, CB₁R/CB₂R expressed by microglia and inhibit cytokine production. THC modulates these receptors. Therapeutic inhibitors that target eCB hydrolysis result in increasing local eCB levels and activity at their targets.

Figure 6:. Examples of THC bioactivity in rodents.

A] “Classic tetrad” behaviors triggered by CB₁R agonists. B] Recent experimental approaches to study THC self-administration. C] Behavioral changes induced by THC in rodents with translational relevance to humans.

Figure 7:. CB₁R-dependent impact of THC on the developing brain during adolescence.

A] CB₁R are expressed by progenitor cells and their activation by THC can trigger apoptoptic cell death, and impair the development of radial glial cells and postmitotic neurons. B] THC activation of CB₁R expressed by mature neurons affects their phenotype and neurotransmitter release. C] CB₁R expressed by mature pyramidal neurons and inhibitory interneurons control the excitatory/inhibitory transmission balance in several brain areas, including prefrontal cortex (PFC), nucleus accumbens (Nac), ventral tegmentum area (VTA). THC also interacts with 5HT1A receptors in the dorsal raphe nucleus (DRN). D] PFC, Nac and VTA in human adolescents undergoes significant development and maturation into adulthood.

Figure 8:. Molecular targets modulated by CBD.

A] CBD is a negative allosteric modulator of CB₁R that is endogenously activated by 2-AG and AEA, an antagonist of GPR55 that is endogenously activated by lysophosphatidyl inositol (LPI) and activate 5HT1A that is endogenously activated by serotonin. B] CBD is an agonist at TRPV1 that is activated by eicosanoids (Eico) and changes in H⁺, a positive allosteric modulator of GABA_AR that is activated by GABA and endogenously allosterically modulated by 2-AG, and a blocker of ENT-1 transporters that carry adenosine.

Figure 9:. LPI-GPR55 Endogenous signaling.

LPI is produced by PLA1/PLA2, activates GPR55 and is inactivated by LysoPLA and LysoPLD. CBD antagonizes GPR55, as well as the antagonist CID160200465.

Figure 10:. THC and CBD bioactivity occurs along continuum.

THC exhibits promising therapeutic response for the treatment of chronic pain (green), , potential harm reduction properties in the context of addiction (gray), and triggers impairing effects and enhances the incidence of mental health disorders (red). CBD exhibits promising therapeutic response for the treatment of epileptic seizures, autism, sleep quality and chronic pain, potential harm reduction properties in the context of addiction, and triggers side effects when used at high dose.