Kava Science Kava and Norepinephrine

[Saghloqh]

I'm wondering if anyone knows which kavalactones are responsible for the norepinephrine reuptake inhibitions which kava seems to show. I've recently been experimenting with kava but unfortunately the effects of the norepinephrine are causing enough anxiety to drown out any positive effects. I've tried a few different batches of kava and one of them had significantly less of those symptoms (although they were still there). If the kavalactone responsible could be isolated, it might be possible to either find strains that contain less of it or find a prep method which pulls less of it.

I'm particularly sensitive to stimulant effects, and have GAD. The feeling is pretty distinctively a fight-or-slight response ("pit-in-the-stomach" feeling, increased heart rate). Hopefully I've just had some bad batches with subpar kavalactone profiles (I'm going to pick up some acetone tomorrow and see if this current batch is tudei - this current one is pretty bad for the anxiety).

Also just wondering if anyone else has dealt with kava causing anxiety. Does it go away after a while, or have any preparation methods worked to eliminate it? I know everyone has different chemotypes and that means kava isn't for everything, but I would love to make it work because its mechanisms of action are perfect for someone who has anxiety and a history of dependence and abuse with other more mainstream treatments.

Thanks for any information or help. I've lurked around this forum on and off for a few years, and I love the community here.

 

[chandra]

Have you tried different types of kava (heady, heavy, balanced)? They affect each individual differently depending on many factors, so it's hard to suggest one. I know Nene bu GHK is considered to be one of the milder kavas that helps with relaxation and sleep. I can get anxiety from kava, but mine is more dose dependant than strain dependent. I'm good with most kavas in smaller amounts, but most give me anxiety in higher doses. All of the vendors here are known for selling noble kava, so you may want to stick with them. I would suggest using traditional prep, because it seems to have the most physical and mental benefits. Also, if kava doesn't work for you, or in addition to, you could try magnolia and amur cork tree bark. Doesn't give you the feel good feeling like kava does, but it's great for anxiety and sleep.

 

[verticity]

As far as I understand it, kava is an MAO-B inhibitor. That means it inhibits reuptake increases levels of dopamine, but not serotonin or norepinephrine. However, the dopamine reuptake by itself could cause anxiety. The order of MAOI potency for the kavalactones is:
desmethoxyyangonin > methysticin > yangonin > dihydromethysticin > dihydrokavain > kavain
Cultivars that are high in DMY are not commonly sold, but high methysticin is common, and yangonin could also play a role. So your ideal chemotype to avoid this would be something like 425--- or 423---. For some people high kavain can also cause anxiety, I'm not sure why, so your best bet might actually be 24----.
References here: http://kavaforums.com/forum/threads...make-n-n-dmt-orally-active.11546/#post-132714

 

[Saghloqh]

As far as I understand it, kava is an MAO-B inhibitor. That means it inhibits reuptake of dopamine, but not serotonin or norepinephrine.

MAO inhibition is actually a separate mechanism from reuptake inhibition. You are correct that MAO B doesn't metabolize norepinephrine, however I've found a few places around the web that claim that something in kava acts as a reuptake inhibitor of norepinephrine. Doing more research it actually seems like the majority of them are referencing one study: https://www.ncbi.nlm.nih.gov/pubmed/12383029

Unfortunately I cannot get past the paywall. However, I am inclined to believe it is true because over the course of many years I have taken a substantial number of herbs/drugs/substances, and the anxiety I was getting from kava is almost identical to the anxiety I get from NDRI's (norepinephrine-dopamine reuptake inhibitors) that are more selective for the norepinephrine transporter.

I really hope sometime in the future we'll get more scientific studies that focus on the individual kavalactones. They're pretty fascinating compounds and I'm sure some of them would be good models for drug discovery. I personally am really curious about the purported effect of increasing GABAA receptor density, because even a couple years after beating benzodiazepine addiction I'm still experiencing lingering effects. (That might also have something to do with why I'm so sensitive for anxiogenics).

Is there any easy reference for cultivar chemotypes? I remember seeing a thread with basic information somewhere on here, and I'm gonna try to find it again. I'm definitely going to start keeping notes of what I try and see if I can find any patterns.

Thanks for the responses!

 

[verticity]

MAO inhibition is actually a separate mechanism from reuptake inhibition. You are correct that MAO B doesn't metabolize norepinephrine, however I've found a few places around the web that claim that something in kava acts as a reuptake inhibitor of norepinephrine. Doing more research it actually seems like the majority of them are referencing one study: https://www.ncbi.nlm.nih.gov/pubmed/12383029

You are right, MAO inhibition is a different mechanism than re-uptake inhibition.

Good find. I was not aware of that research. The original (and maybe only primary) article on NE reuptake inhibition seems to be this one:

[3H]-monoamine uptake inhibition properties of kava pyrones, Planta Med. 1997 Dec;63(6):548-9

Abstract:

"Three kava pyrones, the natural compounds (+)-methysticine and (+)-kavain, and the synthetic racemate (+/-)-kavain, were tested concerning their action on in vitro uptake of monoamines in synaptosomes prepared from the cerebral cortex and hippocampus of rats. (+/-)-Kavain and (+)-kavain were found to potently inhibit the uptake of [3H]-noradrenaline. Uptake of [3H]-noradrenaline was inhibited in the following order of potency: (+/-)-kavain = (+)-kavain > (+)-methysticine, whereas none of the kava pyrones efficiently blocked the uptake of [3H]-serotonin. The results indicate a pyrone-specific non-stereo-selective inhibition of the [3H]-noradrenaline uptake which might be responsible for or, at least, contribute to the psychotropic properties of kava pyrones."

So, kavain is the most potent NE reuptake inhibitor, which could account for the anxiety sometimes caused by high-kavain strains. However these researchers didn't study any kavalactones other than K and M, so it is possible the other ones have the same effect.

 

[ThePiper]

I've never experienced any edginess from Nene (vendor is gourmet Hawaiian kava ) some others to consider that are purely relaxing include panaewa from the same vendor or maybe vula Waka from Kalm with kava

 

[Saghloqh]

You are right, MAO inhibition is a different mechanism than re-uptake inhibition.

Good find. I was not aware of that research. The original (and maybe only primary) article on NE reuptake inhibition seems to be this one:

[3H]-monoamine uptake inhibition properties of kava pyrones, Planta Med. 1997 Dec;63(6):548-9

Abstract:

"Three kava pyrones, the natural compounds (+)-methysticine and (+)-kavain, and the synthetic racemate (+/-)-kavain, were tested concerning their action on in vitro uptake of monoamines in synaptosomes prepared from the cerebral cortex and hippocampus of rats. (+/-)-Kavain and (+)-kavain were found to potently inhibit the uptake of [3H]-noradrenaline. Uptake of [3H]-noradrenaline was inhibited in the following order of potency: (+/-)-kavain = (+)-kavain > (+)-methysticine, whereas none of the kava pyrones efficiently blocked the uptake of [3H]-serotonin. The results indicate a pyrone-specific non-stereo-selective inhibition of the [3H]-noradrenaline uptake which might be responsible for or, at least, contribute to the psychotropic properties of kava pyrones."

So, kavain is the most potent NE reuptake inhibitor, which could account for the anxiety sometimes caused by high-kavain strains. However these researchers didn't study any kavalactones other than K and M, so it is possible the other ones have the same effect.

Awesome find! While as you said it's not exhaustive it gives me a starting point.