Kava and Driving: Poster by Dr. Aporosa

Originally posted on Kava Science Forum Novermber 2017.

Dr. S. Aporosa at the University of Waikato, New Zealand has studied the effect of kava drinking, at traditional levels, on cognitive tests related to driving ability.

Here is his recent poster on the topic.

Cognitive Functions Related to Driving Following Kava Use (pdf)

Reference:
Aporosa, S. “Understanding cognitive functions related to driving following kava (Piper methysticum) use at traditional consumption volumes.” British Association for Psychopharmacology Conference. No. 31 (8). SAGE Publications, 2017.

Conclusion:

• As the six-hour tests session progressed, subtle changes were observed in many of the kava drinker’s, namely psychomotor slowing, a somnolent-like state, altered word pronunciation and a slowing of speech rate.

• The test results were not statistically significant for either reaction time or divided attention measures. To give some context to the reaction time difference found in this study with kava (active 22.10msec slower than mean after 6 hours), consuming 50mg of alcohol (equivalent to the current 0.05 NZ driver blood alcohol limit) slowed driver reaction time by 70msec, which increased to 120msec at 0.08 (the previous limit).

• Discordant to hypothesis, the findings show no correlation between consuming kava at traditional volumes and response latency or impairment on divided attention tasks.

• It is possible the measures selected for this study lacked sensitivity in detecting kava’s effect

He didn’t find statistically significant changes in Reaction Time of Divided Attention, but did note some qualitative behavioral changes which would indicate that people should still avoid driving if they have drunk too much kava. It is important to note that they didn’t actually test driving directly, but used something kind of like a video game setup to test reaction time, etc., as described here:

Vienna Test System Neuro (pdf)

Are endocannabinoid receptors important for kava? Probably not.

Originally posted on Kava Science Forum, Feb. 2017

It is known that one of the kavalactones, yangonin, has very modest affinity for cannabinoid receptors.  So the question of whether this effect contributes in any significant way to kava’s effects comes up sometimes. As far as I can tell, the answer is “probably not.”

First, the affinity of a drug for a receptor can be expressed by a Ki value (the “inhibitor constant”). The lower this number is, the higher affinity the drug has for the receptor. However this number only tells you how much the drug molecule likes to interact with the the receptor. It does not tell you anything about what effect the drug has on the receptor. The drug might be an agonist (i.e., it might stimulate the receptor in the same way as endogenous neurotransmitters), or it might be an a partial agonist, meaning it partially stimulates the receptor, or it might be an antagonist, meaning it binds to the receptor, but does nothing; it just blocks the receptor and prevents it from functioning.

In one paper (A. Ligresti et al, Pharmacological Research, 2012, 66(2) 163-169) they looked at the Ki values of kavalactones for CB1 and CB2 receptors. For yangonin, they found the following values:
CB1: Ki = 0.72 μM (the units are “micromolar”, which refers to the concentration of drug)
CB2: Ki > 10 μM

By way of contrast, the Ki values of THC are (https://en.wikipedia.org/wiki/Tetrahydrocannabinol):
CB1: Ki = 10 nM (“nanomolar”)
CB2: Ki = 24 nM

So in other words, yangonin has about 100 times less affinity for CB1 than THC does, and it’s effect on CB2 is more than 1,000 times smaller. Also, remember, these affinity numbers say nothing at all about what, if any, actual effect yangonin might have on CB1.

The above reference is the only primary source about the yangonin-CB1 interaction that I can find. There are other sources that cite it, but as far as I can tell, that one paper is the only actual research that has been done. I have only seen the abstract, not the complete paper, but in the abstract, no conclusions are drawn about whether yangonin is an agonist, partial agonist, or antagonist of CB1, and nothing is said about how potent the physiological effect might be at all.

What are the effects of potent CB1 agonists?
– Disruption of short term memory
– Distortions in the perception of time and space
– Euphoria
– Paranoia
– Anxiety
among others. Kava can cause euphoria, and occasionally anxiety, although much more often the opposite of anxiety. But kava never causes memory problems, distortions of space and time or paranoia. Now the euphoric effect of kava can readily be explained by other neurological mechanisms having nothing to do with CB1 receptors. Likewise, the occasional anxiety caused by kava can be explained other ways. The fact that kava does not cause memory issues is key, because the memory effects of potent CB1 agonists or partial agonists are specifically caused by the effect of stimulating CB1 receptors on the hippocampus. Kava has no such effect, which suggests that either it is not a potent agonist/partial agonist of CB1, or it could be an antagonist.

So, I really don’t think that the endocannabinoid system plays any significant role in the pharmacology of kava, or in it’s subjective effects. Is it possible that the effect of yangonin on CB1 receptors has some very subtle influence on the overall kava experience? Yes, it is possible, but far from proven, and even if that were the case, it would likely a small role relative to the kava’s other pharmacological actions.

But how much yangonin is actually in a shell of kava? How would the potential effects of this on CB receptors compare to THC, considering that a “standard dose” of THC is 10 mg?

A strong shell of kava can contain up to 500 mg total of kavalactones. Yangonin is typically 10-20% of the total KLs. That’s about 75mg of yangonin per shell.   The maximum amount that most people would drink at once would be something like 4 shells, which would contain approx 300 mg of yangonin in total. Since yangonin has 100 times less affinity for CB-1 receptors, that would be equivalent to the affinity of 3 mg of THC, significantly less than a single “standard dose” of THC.  However, we also need to remember affinity does not tell you anything about effects. THC itself is normally a partial CB1 and CB2 agonist, but can possibly act as a full agonist on certain neurons (See https://www.ncbi.nlm.nih.gov/pubmed/20417220 ).  (Synthetic full agonists have been made, and those are quite potent and dangerous)  Based on kava’s observed lack of cannabis-like effects, it is reasonable to assume that yangonin is not a full CB1 agonist, but either a partial agonist with a much weaker effect than THC, or an antagonist, in which case it would have either no effect or an opposite effect.

Another factor that tends to make me think that yangonin is not a full CB1 agonist is the fact that it was the only one of the main natural kavalactones found to have any CB affinity.  Ligresti et al also tested a bunch of synthetic KL analogs and found nothing besides yangonin with any affinity.  Normally structurally analogous chemicals tend to have similar pharmacological activities, varying in degree depending on the specific chemical.  This is the case with the kavalactones effects on anion  and cation channels, for example.  The fact that yangonin has very weak CB affinity, whereas the other structurally similar KLs have practically none suggests to me that  yangonin’s affinity is basically a fluke maybe due to some specific detail about it’s structure, and not a general effect of the KLs.  In other words, yangonin is barely a CB1 ligand.  Now, saying something barely has any affinity is not the same as saying it functions as a partial agonist or antagonist: that conclusion is just intuition.  I would be curious to see more research about this to prove or disprove my intuition in the preceding paragraph (as well as to simply replicate the result by Ligresti, which so far seems to be unique)..

Kava promotes acetylcholine mediated behavior in worms?

Originally posted on Kava Science Forum, April 2017

Undergraduate research FTW.

Students’ Discovery Draws Interest From International Scientific Community

Quote:
“The biology lab tucked away in Snyder Hall of Science on the Greenville College campus may look unremarkable, but looks can be deceiving. There, students have discovered a potential key to relief for sufferers of neurological disorders. Their work has drawn international attention.

Juliana Phillips ’17, Kellie Steele ’18 and Michael Shawn Mengarelli ’15 recount their recent discovery in The Journal of Experimental Neuroscience, a peer reviewed international journal. Assistant Professor of Biology Bwarenaba Kautu supervised their work with help from Eric Nord, also assistant professor of biology.

The trio discovered that chemicals in kava seem to affect the transmission of acetylcholine, an important neurotransmitter that is critical to vital functions like cognition, learning and memory, movement, muscle contractions and heartbeat.

“Many psychiatric and neurological disorders have been linked to problems with the transmission of acetylcholine,” Kautu explains. “To the best of my knowledge, our research team is most likely the first in the world to show the link between kava metabolism and acetylcholine transmission in an intact living eukaryotic nervous system (neuromuscular junction). These students are instrumental in this discovery.””

 

From the paper:
“The inhibitory-excitatory balance at the C elegans NMJ is maintained by the opposing actions of GABA and ACh. When the level of ACh signaling (excitation) is substantially greater than the level of GABA transmission (inhibition) at the C elegans NMJ, this results in muscle hypercontraction, which can manifest as a convulsion or paralysis. In our study, we showed that treatment of C elegans with kavalactones resulted in convulsions and paralysis (Figure 1). We hypothesized that these responses are indicative of elevated or prolonged ACh transmission at the NMJ.”

Kava is normally thought of as acting in a GABAergic way, so this result is the opposite of what one would expect.

Interestingly, they noted that kavain has a different effect on worms than the other KLs.

Citation:
Kautu, Bwarenaba B., et al. “A Behavioral Survey of the Effects of Kavalactones on Caenorhabditis elegans Neuromuscular Transmission.” Journal of experimental neuroscience 11 (2017): 1179069517705384.

Full text available here:
http://journals.sagepub.com/doi/full/10.1177/1179069517705384

Practical considerations for an inexpensive field instrument for UV kava testing

Originally posted on Kava Science Forum, Feb. 2017

Here are some detailed thoughts about how to build a practical and not too expensive instrument that could be used in the field based on Lebot and colleagues recent article about a method for testing for noble kava my measuring the absorbance of extract at 250 and 290 nm.

An inexpensive field instrument for deep UV kava testing (pdf file attached)