Understanding Cannabis Ligands at CB1
A ligand is a molecule that produces a signal by binding to a site on a target protein. There are 6 types of ligands that can bind to the CB1 receptor, and these ligands can bind to different types of sites on the CB1 receptor. The main binding site is called the orthosteric site. THC, anandamide, and many other cannabinoids bind to the orthosteric site. There also exists a secondary binding site called the allosteric site. Ligands that bind to the allosteric site cannot directly activate the CB1 receptor, but they can increase or decrease the activity of agonists or partial agonists that bind to the orthosteric site.
The 6 types of ligands that bind to CB1 are:
Full Agonists Full agonists activate the CB1 receptor to the fullest extent possible. Many synthetic cannabinoids (such as HU-210, which is included in Spice) are full agonists. Full CB1 receptor activation is not desirable because of the frequency and severity of adverse side effects.
Partial Agonists Partial agonists activate the CB1 receptor, but not to full capacity. THC is a partial agonist. Partial agonists and full agonists compete for the same orthosteric binding site on the CB1 receptor.
Neutral Antagonists A neutral antagonist binds to the orthosteric site but does not activate the receptor. It does, however, block agonists from binding. Neutral antagonists do nothing on their own in the absence of an agonist. CBD, at very high doses can bind very weakly to the orthosteric binding site and, in this scenario, is a neutral antagonist.
Inverse Agonists G-protein coupled receptors have constitutive activity—they have a baseline level of signaling activity even in the absence of an agonist. An inverse agonist not only blocks agonist binding, but also inhibits this constitutive activity . Rimonabant is an inverse agonist at the CB1 receptor. Rimonabant was approved only for a short time in Europe to treat obesity, but was pulled from the market when depression and suicidality were observed.
Positive Allosteric Modulators Positive allosteric modulators bind to the allosteric site and amplify the effect of an agonist by increasing agonist binding or by increasing receptor signaling. One example is molecule ZCZ011, which reduces neuropathic pain in mice with no observed psychoactive effects .
Negative Allosteric Modulators Negative allosteric modulators decrease agonist binding or receptor signaling. When it binds to the allosteric site, CBD is a negative allosteric modulator and can mitigate the adverse effects of THC, such as the lethargy and psychoactivity. Another example is pregnenolone, which is an endogenous steroid that reduces the effects of THC .
Additional suggested reading: http://profofpot.com/endocannabinoid-receptors/
 https://www.nature.com/articles/npp2015148 via prof of pot
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/ via prof of pot