atara
Bluelighter
In the beginning, it was suggested that cannabidiol is a cannabinoid antagonist. However, its affinities for the CB1 and CB2 receptors are in the micromolar range, making them irrelevant at realistic doses.
Later it was suggested that cannabidiol acts as a 5-ht1a partial agonist. However, a closer reading of the original findings shows that the 5-ht1a affinity is also in the micromolar range, probably as weak as 10 µM:
Other targets such as GRP55 and the TRP family of vanilloid receptors were also suggested, but its affinity at these receptors is no better than 150 nM:
But it was also determined that cannabidiol acts as a partial agonist at D2High, the dopamine receptor implicated in the treatment of schizophrenia, with an affinity of 11 nM, and that this affinity is correlated with its action against schizophrenia:
www.nature.com
Surprisingly, it was missed until around 2016 that a well-known drug binds to an extremely well-known monoamine receptor. The partial agonist activity of cannabidiol supposedly resembles that of aripiprazole (Abilify), but without any of the other effects of aripiprazole (antagonist at 5-ht2a, inverse agonist at 5-ht2b, partial agonist at 5-ht2c, 5-ht1a, and DRD3). However, cannabidiol is far more selective than aripiprazole in achieving this activity, since aripiprazole is roughly equipotent at DRD2 and 5-ht2b, while cannabidiol's second-highest receptor affinity is more than ten times as weak as its DRD2 affinity.
This is only moderately disappointing: prior reports suggested that cannabidiol had antipsychotic action against schizophrenia by an "unknown" mechanism, but this turns out to be wrong. Cannabidiol has action against schizophrenia by the normal mechanism. Because it is a partial agonist, we may also expect efficacy in the management of social anxiety (which is exacerbated by DRD2 antagonists) and autism (which is commonly managed with aripiprazole). But, of course, these actions of cannabidiol are known!
Unfortunately, there are still studies reporting that cannabidiol's activity in schizophrenia is not DRD2-dependent. This turns out to be false; it is just another example of the case where a tuned partial agonism has fewer side effects than a full agonist or full antagonist. So spread the word!
EDIT: It appears that cannabidiol is also a negative allosteric modulator at CB2 (IC50 = 3 nM), reducing the activity of agonists by approximately 50%:
So I would have to partially retract the claim of "moderately selective", although the action at CB2 is not overwhelming (agonists still have significant activity).
Later it was suggested that cannabidiol acts as a 5-ht1a partial agonist. However, a closer reading of the original findings shows that the 5-ht1a affinity is also in the micromolar range, probably as weak as 10 µM:
Other targets such as GRP55 and the TRP family of vanilloid receptors were also suggested, but its affinity at these receptors is no better than 150 nM:
But it was also determined that cannabidiol acts as a partial agonist at D2High, the dopamine receptor implicated in the treatment of schizophrenia, with an affinity of 11 nM, and that this affinity is correlated with its action against schizophrenia:
Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose - Translational Psychiatry
Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors...
www.nature.com
Surprisingly, it was missed until around 2016 that a well-known drug binds to an extremely well-known monoamine receptor. The partial agonist activity of cannabidiol supposedly resembles that of aripiprazole (Abilify), but without any of the other effects of aripiprazole (antagonist at 5-ht2a, inverse agonist at 5-ht2b, partial agonist at 5-ht2c, 5-ht1a, and DRD3). However, cannabidiol is far more selective than aripiprazole in achieving this activity, since aripiprazole is roughly equipotent at DRD2 and 5-ht2b, while cannabidiol's second-highest receptor affinity is more than ten times as weak as its DRD2 affinity.
This is only moderately disappointing: prior reports suggested that cannabidiol had antipsychotic action against schizophrenia by an "unknown" mechanism, but this turns out to be wrong. Cannabidiol has action against schizophrenia by the normal mechanism. Because it is a partial agonist, we may also expect efficacy in the management of social anxiety (which is exacerbated by DRD2 antagonists) and autism (which is commonly managed with aripiprazole). But, of course, these actions of cannabidiol are known!
Unfortunately, there are still studies reporting that cannabidiol's activity in schizophrenia is not DRD2-dependent. This turns out to be false; it is just another example of the case where a tuned partial agonism has fewer side effects than a full agonist or full antagonist. So spread the word!
EDIT: It appears that cannabidiol is also a negative allosteric modulator at CB2 (IC50 = 3 nM), reducing the activity of agonists by approximately 50%:
So I would have to partially retract the claim of "moderately selective", although the action at CB2 is not overwhelming (agonists still have significant activity).
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