Serotonin Receptors The serotonin 5-HT1A receptor is one of the most widespread in the CNS, found in high levels in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus. CBD is a full agonist at the 5-HT1A receptor, although with relatively low potency in the microM range. THC, even at high concentrations, did not bind the 5-HT1A receptor. However, both CBD and THC may activate 5-HT1A receptors through indirect mechanisms.
5-HT1A receptor activation is associated with decreased blood pressure, decreased heart rate, and decreased body temperature. 5- HT1A agonist drugs( such as buspirone) can relieve anxiety and depression. The 5-HT1A receptor is also important in mediating the anti-depressant effects of SSRIs and even MDMA. 5-HT1A activation is also antiemetic and analgesic. Finally, 5-HT1A activation may improve symptoms of schizophrenia and Parkinson’ s Disease. On the other hand, 5-HT1A receptor activation can also cause impaired learning and memory.
The serotonin 5-HT2A receptor is important for emotions, learning, and memory. THC does not bind the 5-HT2A receptor. CBD is a weak partial agonist, with over 8 μM of CBD required to elicit a significant effect. Since THC can activate the 5-HT2A receptor through CB1 receptor dimerization, this may be more important than any direct effect of CBD. The serotonin 5-HT3 receptor is involved in pain transmission and mood disorders. 5-HT3 antagonists are used for chemotherapyinduced nausea and vomiting. Both THC( IC50 = 38 nM) and CBD( IC50 = 600 nM) are potent negative allosteric modulator of 5- HT3A. This inhibition may also be partly responsible for the analgesic and anti-nausea effects of cannabinoids. This inhibition of the 5-HT3 receptor is shared with endocannabinoid anandamide.
Dopamine Receptors The dopamine D2 receptor has a role in many brain functions, but is particularly important in schizophrenia. Antipsychotic medications act upon the D2 receptor. The D2 receptor can exist in a state of high affinity for dopamine( D2High) or a state of low affinity for dopamine( D2Low). Elevated levels of the D2High receptor are associated with schizophrenia.
CBD has shown antipsychotic properties both by itself and when added to an ongoing treatment regimen. To determine the mechanism through which CBD exerts its antipsychotic effects, the binding of CBD to D2 receptors was tested. CBD was a potent( IC50 = 66 nM) partial agonist of the D2High receptor, which is a characteristic shared with some other antipsychotics such as aripiprazole.
The partial agonist activity may explain some of the reported side effects of CBD, such as drowsiness, diarrhea, decreased appetite, and fatigue.
Although binding of THC was not tested, there is no rationale to think that THC would directly interact with D2 receptors. However, THC can indirectly modulate D2 receptors via receptor dimerisation.
Opioid Receptors Both THC and CBD were reported to be negative allosteric modulators of the mu opioid receptor and delta opioid receptor. They decreased binding of opioid ligands, but the potency was quite low( EC50 = 4-5 μM). However, since only ligand binding and no signalling studies were performed, the significance of this remains unknown. Dimerization with the CB1 receptor may play a more important role in modulating these opioid receptors than direct modulation by Phytocannabinoids.