Why are some noids so horrendous when some are so benign? Should we be more wary of lesser known natural cannabinoids now we know the possible dangers of novel synthetic cannabinoids gone wrong?

What about the structure/action on the human brain makes makes modern noids so dangerous when compared to previous noids and thc?

How can we get such radically different responses from chemicals that act on the same parts of the brain?? (Our cannabinoid receptors, often specifically the CB1 receptor)

I know about how thc is a partial agonist, where most noids are full agonists of the CB1 receptor, but JWH-018 was a full agonist. So that alone doesn't explain the neurotoxicity of modern noids.

We have all these neurotoxic synthetic noids from hell that cause seizures. And acting on the same receptors we have thc and cbd, both help TREAT seizures! And cbd is neurogenerative! What abouti their differences in action on the human body explain this night and day difference?

Honestly the fact that we can synthesize a huge number of noids that act on the cannabinoid receptors of our bodies that are so god-awful that they can give permanent brain damage with one dose, makes me wary of even natural cannabinoids. We know thc is relatively safe because there are a huge number of people that have done it for a very long time (however it does seem to affect working memory over time, and some people can develop depersonalization disorder). But all these minor cannabinoids in cannabis that they're breeding to obtain lots of these days: CBG, thcv, delta-8 Thc, etc. Are these new cannabinoids that are becoming available through genetic breeding safe? How do we know they will not be neurotoxic and potentially deadly like the synthetic noids?

Not to mention Yangonin in kavakava being smoked for the first time in the historical use of the plant, and polyphenols concentrated up in green tea extract taken as a dietary supplement. Both plants can cause liver damage if you take the extract in excess. The cannabinoid EGCG in green tea extract is to blame for the liver damage when it is taken in excess. I don't think we have narrowed down the kavakava liver damage to the cannabinoid Yangonin yet, but I wouldn't be surprised if it was the culprit.

Why are noids so much worse? And should we be more wary of natural cannabinoids now that we know the possible horrors of what synthesized cannabinoids are capable of?

I'd love to hear this community's thoughts on this. Thanks!

I'm a pharmacologist studying synthetic cannabinoids. The exact reasons /mechanisms that synthetic cannabinoids have such a different effects compared to THC/cannabis is not completely understood but we think it relates to a few key aspects. First, synthetic cannabinoids typically have very high affinity for cb1, generally anywhere from 10 to 100 fold greater than THC. Affinity is primarily driven by a drug's off rate so if these compounds park themselves on the receptor for a long time (residency time) they potentially can keep the receptor active for longer, which is important in a system not at equilibrium, ie a living system, where concentration varies over time as drug is absorbed , distributed, metabolized, excreted. Second, as you mentioned synthetic cannabinoids typically have greater efficacy than THC meaning a single interaction with a receptor can produce a larger effect than could occur with cannabis. Third, receptors signal through many pathways and different drugs can exhibit signaling bias where one pathway is activated more than another. Not much is known yet about signaling bias at cannabinoid receptors, let alone synthetic cannabinoids. Fourth, metabolites continue to activate the receptor and some synthetic cannabinoids actually get converted very quickly so we're now starting to study those more and it's being suggested that metabolites may be involved in some of the adverse effects. Finally, they may not be producing their adverse effects at cannabinoid receptors. It's been suggested by a few groups in mouse studies that the seizure activity is via cb1, which is a little counter intuitive considering that cannabinoids are typically thought to be protective and the cb1 inverse agonist rimonabant was reported to exacerbate seizures when it was briefly being used in humans. But that gets very complicated because depending upon which neuronal systems are being affected, if cb1 receptors are located in excitatory and inhibitory neurons that converge, differences in receptor populations can result in one effect at low concentrations and/or efficacy and opposite effect at high concetrations/efficacy. But other adverse effects like cardiotoxicity could be via some non cannabinoid mechanism.

But yeah, cannabis for the most part is safe so if you're going to insist on getting high that would be better. But it can still cause addiction /dependence, affect fetal development, exacerbate psychosis and potentially promote development of schizophrenia in susceptible individuals.

Thank you for your input, this is really educational! Different metabolites causing the horrible side effects makes a lot of sense. And I hadn't considered signaling pathways.

Thanks again for taking the time to explain!