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Kava Fact of the Day Evidence for a reverse tolerance effect?

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
A little evidence for reverse tolerance in kava.

That’s right, kava lovers, we’re attacking that great kava mystery today, reverse tolerance. I went about this by continuing to read through research regarding kava keeping in mind to note effects that don’t seem to turn up except for after a specific period of time, possibly lending credibility to the idea of reverse tolerance.

What is reverse tolerance?

Reverse tolerance is a phenomenon in which following repeated use of the same compound behavioural, physiological, or cellular responses increase, rather than decrease over time [1]. The most common understanding of reverse tolerance comes to us by the study of alcoholic disease progression in alcoholic hepatitis. Over time ethanol damages liver structures and prevents enzyme production. This reduces the liver’s ability to process alcohol and as such decreases the amount needed to provide physiological effects.The development of this sensitization is an essential component of the positive reinforcement theory of alcohol addiction in humans [2].

So what is “reverse tolerance” with kava?

This is known as the strengthening of kava’s effects to a point. This is usually seen after a few weeks or a month of continual daily drinking at which point further anxiolytic potential is unlocked.

Here’s where we get into the not so researched side of kava. Reverse tolerance is a continually debated topic. Some kava drinkers see this effect, while others don’t. Here I’m going to attempt to add some evidence of kava’s effect on acetylcholine with the hypothesis that the delay in action here may speak for some of the reverse tolerance effects we’ve seen.

The Study:


In 2010 a study was performed to understand the effect of anxiolytic actions and safety of kava. This was performed orally, IN VIVO at 75mg/kg, with rats being the subject [3]. The target of this study was the amino acid metabolizer known as acetylcholinesterase. This chemical immediately breaks down acetylcholine into acetic acid, and choline [4]. It’s important to understand the function of this compound in this scenario. When acetylcholinesterase activity is inhibited, the concentration of acetylcholine in the synapse will remain higher than normal [5]. Through a complex function of cascading actions it is thought that this higher than normal amount of acetylcholine may begin to interact with GABA receptors, causing the increase in release of GABA at the synapse, further elucidating anti-anxiety properties [6].

From the study’s presented data, it can be suggested that the decrease in acetylcholinesterase after the time frame of 4 weeks may mediate an additional anxiolytic effect from kava extract by increasing the cholinergic transmission in specific brain areas. This study showed that this effect was seen to occur the fastest in the cortex followed by the hippocampus and striatum.

Summary:

There is initial evidence that kava extract may show an ability to reduce the breakdown of acetylcholine, leading to an increased efficacy of kava overall. Studies have shown that this effect takes around 4 weeks of continual kavalactone consumption to appear, and as such may speak to the emergence of a stronger effect over time, also known as reverse tolerance.



[1] Tomek, Seven E., and M. Foster Olive. 2018. “Social Influences in Animal Models of Opiate Addiction.” International Review of Neurobiology 140 (July): 81–107.
(https://doi.org/10.1016/bs.irn.2018.07.004)

[2] Tran, S., and R. Gerlai. 2017. “Chapter 7 - Zebrafish Models of Alcohol Addiction.” In Addictive Substances and Neurological Disease, edited by Ronald Ross Watson and Sherma Zibadi, 59–66. Academic Press.
(https://doi.org/10.1016/B978-0-12-805373-7.00007-4)

[3] Noor, Neveen A. 2010. “Anxiolytic Action and Safety of Kava: Effect on Rat Brain Acetylcholinesterase Activity and Some Serum Biochemical Parameters.” African Journal of Pharmacy and Pharmacology 4 (11): 823–28.

[4] Trang, A., & Khandhar, P. B. (2021). Physiology, acetylcholinesterase. In StatPearls. StatPearls Publishing.
(http://www.ncbi.nlm.nih.gov/books/NBK539735/)

[5] Acetylcholine. Chemistry Explained. (n.d.).
(http://www.chemistryexplained.com/A-Ar/Acetylcholine.html)

[6] Yamamoto, Sumii, Junko Yamada, Shinya Ueno, Hisahiko Kubota, Tomonori Furukawa, Seiji Yamamoto, and Atsuo Fukuda. 2006. “Insertion of α7 Nicotinic Receptors at Neocortical Layer V GABAergic Synapses Is Induced by a Benzodiazepine, Midazolam.” Cerebral Cortex 17 (3): 653–60.
(https://doi.org/10.1093/cercor/bhk010)
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
So we can say that it’s possible in some users?
From what I'm reading, the increase in effect seems to be quite real. This coupled with MAO-A and MAO-B inhibitory properties which also require time to show up, makes me think maybe there's something in there that speaks to what we know as the "reverse tolerance". Not to be confused with initial tolerance which is where the user may find it difficult to feel effects in the beginning.

Now, whether you will notice this is a completely different story. I honestly think those with issues such as anxiety and depression may see this "second wave" of kava effects more so than someone who's neurotransmitters are balanced.
 

LyndaKaye

Kava Curious
I see that. I wonder if addicts also may see this second wave. I definitely feel like I had a problem trying to see Kava’s effects at the beginning.
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
I see that. I wonder if addicts also may see this second wave. I definitely feel like I had a problem trying to see Kava’s effects at the beginning.
I think addicts would see this as well. Of course this is totally my opinion, and I have no sources for this, so it's one to take with some salt. I think the ones that are likely never to see it, or never notice it, are people who come to kava for recreation and only use it sporadically (as in, not daily). The key being that kava use has to be continual for these secondary effects to build up.

The initial tolerance is debatable, and there isn't really any evidence in literature that would speak to a real chemical initial tolerance effect. It's slowly becoming an accepted understanding that prep and expectations are the biggest factors in "feeling it" when you first start. Newbies can easily use too little kava, not enough agitation, or just simply have no clue how to go about making a proper batch. I consider people in this phase when I see them asking about using a French press. Another is the aluball. It's an awesome device....unless you don't follow the directions, and we all know how often people read directions. I've seen quite a number of issues with people starting out with it, cramming the balls completely full, and then reporting that they didn't feel anything. Kava does have a less gentle learning curve when compared to other intoxicants :)
 

LyndaKaye

Kava Curious
True life! I’ve learned how to mix and now spend a lot of time at the lounge so I’m set! But I have friends that still never feel anything. So I think you’re right, it’s all about continued use!
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
True life! I’ve learned how to mix and now spend a lot of time at the lounge so I’m set! But I have friends that still never feel anything. So I think you’re right, it’s all about continued use!
It's truly something I wish a little research would be done on. Instances where you made the kava, and you know the strength, but the person still reports not feeling anything makes me want to know more. That specific set up I can't explain. Are there full on "non-responders" to kava? This is a great question I'd love to see an attempt at answering. There's been over 160 years of kava research, but questions still remain.
 

LyndaKaye

Kava Curious
It's truly something I wish a little research would be done on. Instances where you made the kava, and you know the strength, but the person still reports not feeling anything makes me want to know more. That specific set up I can't explain. Are there full on "non-responders" to kava? This is a great question I'd love to see an attempt at answering. There's been over 160 years of kava research, but questions still remain.
Yea same here. I wish there was more research! Maybe we should do our own test studies! There are some strains that I have found to be consistent across all the users I’ve experienced them with. But with kava, in general, I have found there to be other variables; how empty of a stomach, how much water you drank, your mood, the strain, warm/cold water, how long you mixed, etc.
 

The Kap'n

The Groggy Kaptain (40g)
KavaForums Founder
Yea same here. I wish there was more research! Maybe we should do our own test studies! There are some strains that I have found to be consistent across all the users I’ve experienced them with. But with kava, in general, I have found there to be other variables; how empty of a stomach, how much water you drank, your mood, the strain, warm/cold water, how long you mixed, etc.
True true. It's quite rare, and usually I see people respond with "oops, looks like using hot water did the trick" or "I waited longer after eating and it finally worked" when they figure it out, but once in a blue moon you'll find someone who says they feel nothing no matter what they try. These "hard heads" either have something going on metabolically that's chewing through kava so fast it never reaches the appropriate place in the body to work, or they have a rather extensive background in drug or alcohol use, and are looking for kava to produce parallel effects. Obviously kava falls short of that (thankfully) and some people may interpret this as being "weak" or "inactive". Or they're just not telling the truth and are completely whacked out of their mind, lol.
 
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