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.
• 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:
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.
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
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)..
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.
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.
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.
I’m in the process of copying my content over from the Kava Science Forum. The original intention of that forum was to be a place for discussion of scientific aspects of kava. However, it turned out for the most part to just be my personal blog, with occasional comments from a couple other folks from Kava Forums. This blog will still allow me to post my occasional sciency posts, and will still allow interested people to comment, but with less overhead than a full-blown forum.
Originally posted on Kava Science Forum, April 2017
On another forum, a member asked if it was OK to drink kava while recovering from surgery, due to the possibility that kava could act as a “blood thinner.” This is a summary of the research that I learned about while trying to answer this question. There is not much research on this topic, but there have been a couple scientific papers that suggested kava could act as a “blood thinner” (meaning it could inhibit blood platelets from coagulating, similar to the action of aspirin and other drugs) due to the COX-inhibiting effect of some of it’s constituents.
First, what is “COX?”
Cyclooxygenase, abbreviated to COX, is an enzyme that is involved in the production of prostaglandins and thromboxanes, which are hormone-like chemicals in the body that are involved with blood platelet aggregation (clotting). If the activity of COX is inhibited, it indirectly leads to interference with blood clotting. The most common example of COX inhibiting drugs are non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and ibuprofen.
(1) The following paper demonstrates that the kavalactones in kava have a COX-inhibiting effect that is similar in magnitude to aspirin or ibuprofen:
“Cyclooxygenase enzyme inhibitory assay-guided purification of ethyl acetate extract of Piper methysticum (kava kava) roots yielded six biologically active compounds (1–7), which were purified using MPLC, preparative TLC and HPLC methods. These compounds were also evaluated for antioxidant activities. Dihydrokawain (1) and yangonin (6) showed the highest COX-I and COX-II inhibitory activities at 100 µg/ml, respectively. The lipid oxidation assay did not reveal antioxidant activities for demethoxyangonin (2), dihydrokawain (1), kawain (4), dihydromethysticin (5) or methysticin (7) at 50 µg/ml. The antioxidant activities of flavokawain A (3) and yangonin (6) could not be tested in the lipid oxidation assay due to solubility problems. However, yangonin and methysticin showed moderate antioxidant activities in the free radical scavenging assay at 2.5 mg/ml. “
This figure from the paper compares the COX inhibiting activities of the kavalactones to ibuprofen, naproxen and aspirin:
Now, what I don’t know is if 100 μg/ml is actually a normally occurring physiological concentration of the chemicals in kava.
(2) This is another paper by the authors of the above paper. They show that other chemicals in kava, in addition to kavalactones, can also inhibit COX, including FKB:
Abstract: “Milled Piper methysticum roots were extracted sequentially with hot water and methanol. Cyclooxygenase (COX) enzyme inhibitory assay directed purification of the methanol extract yielded bornyl esters of 3,4-methylenedioxy cinnamic acid (1) and cinnamic acid (2), pinostrobin (3), flavokawain B (4), and 5,7-dimethoxyflavanone (5). The structures of compounds 1−5 were accomplished by spectral experiments. The aqueous extract contained previously reported kava lactones, as confirmed by TLC analysis. Compounds 3 and 5 were isolated for the first time from kava kava roots. Compound 4 showed the highest COX-I inhibitory activity at 100 μg/mL. All the compounds tested gave good COX-I and moderate COX-II enzyme inhibitory activities at 100 μg/mL. This is the first report of COX-I and -II inhibitory activities for compounds 1−5.”
(3) An older paper specifically about kavain (also concludes that kavain is a COX inhibitor):
Abstract: “(+)-Kavain, a 4-methoxy-alpha-pyrone prepared from Piper methysticum Forst. (Piperaceae), was investigated regarding its assumed antithrombotic action on human platelets which was deduced from its ability to suppress arachidonic acid (AA)-induced aggregation, exocytosis of ATP, and inhibition of cyclooxygenase (COX) and thromboxane synthase (TXS) activity, the latter two effects being estimated from the generation of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), respectively. Exogenously applied AA (100 mumol/l) provoked a 90% aggregation of platelets, the release of 14 pmol ATP, and the formation of either 220 pg TXA2 or 43 pg PGE2, each parameter being related to 10(6) platelets. An application of (+)-kavain 5 min before AA, dose-dependently diminished aggregation, ATP-release, and the synthesis of TXA2 and PGE2 with IC50 values of 78, 115, 71, and 86 mumol/l, respectively. The similarity of the IC50 values suggest an inhibition of COX by (+)-kavain as primary target, thus suppressing the generation of TXA2 which induces aggregation of platelets and exocytosis of ATP by its binding on TXA2-receptors.”
(4) Also see the following paper about a “TNF‐α” mediated anti-inflammatory activity of kavain and some synthetic derivatives:
Pollastri, Michael P., et al. “Identification and Characterization of Kava‐derived Compounds Mediating TNF‐α Suppression.” Chemical biology & drug design 74.2 (2009): 121-128.
“There is a substantial unmet need for new classes of drugs that block TNF-α-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-α secretion in lipopolysaccharide (LPS)-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-α inducing transcription factor Lipopolysaccharide Induced TNF Alpha Factor (LITAF). Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was found to render mice immune to lethal doses of LPS. Kavain displays promising pharmaceutical properties, including good solubility and high cell permeability, but pharmacokinetic experiments in mice showed relatively rapid clearance. A small set of kavain analogs was synthesized, resulting in compounds of similar or greater potency in vitro compared to kavain. Interestingly, a ring-opened analog of kavain inhibited TNF-α secretion in the cell based assay and suppressed LITAF expression in the same cells, whereas the other compounds inhibited TNF-α secretion without affecting LITAF levels, indicating a potential divergence in mechanism of action.”