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 behavioral, 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.