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A Kavalactone Works as a Cannabinoid

A

AlphaMethylPhenyl

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Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand.

Abstract
To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB₁ receptor with a K(i)=0.72 μM and selectivity vs. the CB₂ receptor (K(i)>10 μM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB₁ receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant.
Copyright © 2012 Elsevier Ltd. All rights reserved.



http://www.ncbi.nlm.nih.gov/pubmed/22525682
 
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Well, that's awfully weak. That's in micromoles. usually we're talking in the low nanomolar range. That's very high nanomolar range.
 
Ok. Still interesting though. I just assumed because I'd heard it was one of the six major kavalactones that it had an appreciable effect.
 
Given the doses people take that should be high enough affinity. Question is whether it's an agonist or not; I guess not, or it's very weak, otherwise people would report getting stoned from it.
 
I do get somewhat stoned from Kava. It altogether feels like a clear-headed cross between booze and weed to me. Of course I'd like to hear what others have to say.
 
skillet said:
Given the doses people take that should be high enough affinity. Question is whether it's an agonist or not; I guess not, or it's very weak, otherwise people would report getting stoned from it.
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Were there half a gram or more of yangonin in a few cups of kava... And it's orally active. For whatever reason oral cannabinoids never seem to work very well- and there aren't any reports of the super-stoned effects an oral overdose produces.

JWH-081 has an affinity of 1.2nM @ CB1.

720nM is way, way, high. Are there ANY cannabinoid agonists with affinity that weak which produce cannabimimetic effects? It's pretty unlikely. By the time you'd have reached an effective concentration for CB1 activation, you're way above the EC50 for whatever other sites it has affinity toward.
 
Hammilton said:
Well, that's awfully weak. That's in micromoles. usually we're talking in the low nanomolar range. That's very high nanomolar range.
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Sure, but doses of kavalactones are usually ~100 mg. I don't think yangonin represents a great starting point, but CB1 -- like NET, MAO-B, and VGICs -- might be yet another contributor to kava's odd effect profile.
 
Right, but at 700x less potent than say JWH-018, 100mg of a mix is nowhere near active at CB1
 
Ho-Chi-Minh said:
I do get somewhat stoned from Kava. It altogether feels like a clear-headed cross between booze and weed to me. Of course I'd like to hear what others have to say.
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I love Kava! Kava gets me preeettty stoney at times. The paste I just got was tried a few days ago. It hit surprisingly fast and felt like a more euphoric benzo like temazepam (obvs. not the same feelings but just a comparison) as it kicked in. I had a good hour long peak. Kava always gives me the most restful sleep and its actually veeerrryyy very deep relaxing sleep. Kava does make me feel a little stoned for sure.
 
This is interesting, and I have been one to say a good kava buzz is like a mix of alcohol and small amount of cannabis. The quiet contemplation as well as sounds and sight getting more sensative. Sort of a peaceful alcohol effect.

I truly believe we've only scratched the surface as to what plants can produce. So many plants, so little time. But lots of room for learning.
 
Totally. I furthermore marvel at basically only two of these plant preparations being used in popular medicine, and even then they're scant.

I notice synergism between the two substances, now.
 
Ho-Chi-Minh said:
Totally. I furthermore marvel at basically only two of these plant preparations being used in popular medicine, and even then they're scant.

I notice synergism between the two substances, now.
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I find Alcohol less effective at time if theres quality Kava around.....anytime I smoke with it or anytime I take it I get a Warm fuzzy itch
 
Depending on distribution in the body, micromolar affinity may be enough for effects to manifest. Ki doesn't tell you the shape of the dose vs response curve either.
 
Right, it effectively gives you a lower limit... which isn't reached at these doses.

Not impossible, but rather unlikely

I wouldn't put any money on this compound's affinity for CB1 having any effect on kava's activity.

Actually, i'd be willing to bet that Rimonabant wouldn't have much effect on responding.
 
Ho-Chi-Minh said:
My experience dictates otherwise, though marginal
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If I were to smoke weed and drink alcohol I'd notice a synergism in their effects, although there's no reason to believe they share some common mechanism of action. Similarly a synergistic effect from combining kava and cannabis doesn't tell you anything about their pharmacology.
 
They do share some common mechanisms from what I've heard

I am talking of a "stoned" effect when simply ingesting kava

It was off-topic
 
Ho-Chi-Minh said:
My experience dictates otherwise, though marginal
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No offense man, but this is exactly the sort of pseudoscientific reasoning that brings down the level of this forum.

I mean, it's like saying "well, it feels like there's more serotonin in this drug" or other nonsense.
You experience doesn't tell you what receptor it's binding to. it doesn't "dictate" anything.

Think of the dozens of random herbs that people have been smoking and claiming produce cannabimimetic effects? hops, damaina, etc. How many actually have any cannabimimetic effects? Pretty much none.

Until someone shows that rimonabant blocks responding, it's way too early to start assuming that it's a cannabinoid or contains a cannabinoid.

Are there any known psychoactive cannabinoids with affinity this weak? I'm not aware of any.

Is Kava positive in the tetrad test? Again, I don't believe so.
 
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