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 .