Honokiol and other CB ligands

[polymath]

There seem to be several natural compounds, including magnolol, honokiol and curcumin, that are either CB1 antagonists or agonists with such a functional selectivity that they don't cause an intoxicating effect. Would this mean that something like curcumin (with black pepper to increase bioavailability) could be used as an antidote to cannabinoids if someone has taken too much of them? Or to test whether something has a cannabinoid mechanism of action, e.g. take nutmeg with curcumin to see whether they cancel each others effects.

Honokiol also binds to GABA-A receptors but doesn't cause a significant benzo like effect, does this mean that it could precipitate withdrawal symptoms if taken by someone who's physically dependent on benzodiazepines?

 

[sekio]

I think the reason e.g. honokiol/curcumin are not very active us because of their very poor BA/metabolic lability.

 

[polymath]

Yeah, it seems curcumin nanoparticle preparations are tested as a formulation that crosses the BBB more easily.

Formulations of Curcumin Nanoparticles for Brain Diseases

Curcumin is a polyphenol that is obtained from Curcuma longa and used in various areas, such as food and textiles. Curcumin has important anti-inflammatory and antioxidant properties that allow it to be applied as treatment for several emerging pathologies. ...

www.ncbi.nlm.nih.gov

When something like valerian root is said to contain benzodiazepine partial agonists, I'd find it more believable if they could demonstrate that it blocks the effects of diazepam or some other full agonist. Otherwise it could just bind to some part of the GABA-A receptor where it doesn't even do anything.

 

[asecin]

what about https://en.wikipedia.org/wiki/Ajulemic_acid or are you interested in CB1 only

 

[polymath]

There's an extensive list of cannabinoid compounds found in natural products in this article:

Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB[1] and CB[2] ) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are ...

www.ncbi.nlm.nih.gov

Even CB1 agonists can have different kind of effects if they selectively activate only one secondary messenger system:

Functional Selectivity at Cannabinoid Receptors - PubMed

It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred...

www.ncbi.nlm.nih.gov

This seems a bit similar to how some dopamine reuptake inhibitors have minimal euphoriant effects but are still effective nootropics or ADHD medications. Or some 5-HT2A agonists having no hallucinogenic effects.

 

[asecin]

well written, good information. not sure why you post questions here when you seem quite able to find your answers by yourself, eventually.
honokiol or magnolol are not exactly prime time for anyone to know much about. personally, i felt a bit of tiredness and slight relaxation effect by taking the patent Relora few times. nothing amazing. definatelly not like benzos at all. they are much more vulgar, hit you straightforward, powerful long lasting sedation.

 

[polymath]

well written, good information. not sure why you post questions here when you seem quite able to find your answers by yourself, eventually.

Mainly to see if anyone's heard anecdotes of some natural product "cancelling" a cannabinoid high... There can even be an antagonist-precipitated WD from cannabinoids, with much worse symptoms that the normal mild withdrawal after quitting excessive cannabis use. However, that only happens if the CB receptor blocker can cross the BBB.

Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist ...

www.ncbi.nlm.nih.gov

Rationale
Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal.
Objective
Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints.
Methods
The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545.
Results
In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC.
Conclusions
These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545.