I drink kava one to three times per week, so I've been wondering...

How long should someone wait between taking an MAO-B inhibiting plant-like Kava Kava before taking an MAO-A inhibiting plant (B. Caapi and Syrian Rue being the primary examples)? How about Caapi/Rue before Kava Kava?

I didn't include passionflower above, just because its mao inhibition seems to be very weak in comparison to rue/caapi. Still, it doesn't hurt to mention it.

Kava inhibits MAO-B. Some reports and discussions indicate that the combination of Kava with Ayahuasca is not a good idea. Results could include serotonin syndrome and all the joys that come along with it, like dying.

https://www.dmt-nexus.me...aspx?g=posts&t=58199

https://wiki.dmt-nexus.m....28MAOI.29_.2B_Kava_kava

The thread below mentions that this is likely because of a combination of harmalas and kavalactones, which would inhibit both MAO-A and MAO-B. So that would be the potential cause of serotonin syndrome, yeah?

https://www.dmt-nexus.me...aspx?g=posts&t=63040

Kava extracts have been shown to bring about MAO-B inhibition in the brains of mice (cortex and substantia nigra) in doses as low as 10mg/kg. Assuming that this is a very pure extract, it might mimic the equivalent of about 10mg of pure kavalactones. These kavalactones seem to be the primary ingredient responsible for MAO-inhibition.

https://pubmed.ncbi.nlm.nih.gov/31539917/

I've found a few sources mentioning that one gram of Kava contains, on average, 100mg of pure kavalactones (10% of the dry weight).

http://entheology.com/fe.../kava-kava-dosage-guide/

"Peak levels occur (for kavain [the primary kavalactone]) at 1.8 hours with an elimination halflife of approximately 9 hours and distribution halflife of 50 minutes."

https://www.reliasmedia....va-i-piper-methysticum-i

The average amount of kavalactone mg per dose is suggested to be about 300mg (about 3g of standard kava powders). 300mg vs. the average human weight, approximately 62 kg… about 5mg/kg. 5mg vs. the 10 mg/kg shown to activate MAO-B inhibition in mice… so it's plausible that even one average dose could have significant interaction with MAO-A inhibiting plants. Important to note that the study does not indicate that lower amounts were inactive. Instead, 10mg/kg was the lowest amount of kava extract tested.

With a two-hour time to peak and a 9-hour elimination halflife, we're down to 150mg at 11 hours, 75mg at 20 hours, 19mg at 38 hours (0.3mg/kg at this point). So that's approximately 38 hours per 3g (one average dose of Kava) until you're looking at near-complete elimination. 47 hours with a 6g dose (19mg ~ 0.3mg/kg approx). 56 hours for 9g (900mg ~ three servings) to reach 14mg (0.2mg/kg).

If similar mg/kg rates apply to mice and humans, and if my math is on point...

The approximate wait between taking Kava and then MAO-A inhibitors (B. caapi, Syrian rue):

38 hours for one 3g dose, + an additional 9 hours for each additional 3g serving before taking an MAO-A inhibitor.

This is my best guess, and of course, there would need to be more research to confirm this. Suppose your bodyweight is really far from the average of 62kg. In that case, it might be helpful to just figure out your own timeline.

The following source simplified my research for the reverse scenario (caapi or rue before Kava):

https://www.sciencedirec...ciences/harmala-alkaloid

"The harmala alkaloids interfere with the protective enzyme MAO for 3–6 hours, before their action is reversed and MAO activity restricted." Let's be safe and assume that this timing probably comes with a 30-minute to a 90-minute peak time when ingested orally...

Approximate wait between taking B. Caapi/Rue and then taking Kava:

4-7.5 hours

Unfortunately, I couldn't find equivalent research for Kava that states how long the MAO inhibition lasts. So, I chose to go the safe route and use the halflife of that primary MAO-inhibiting compound (kavain) as a guideline.

--

Let me know about any corrections and first-hand experiences. Extra mention that a lot of this is guesswork. In reality, the longer you wait between taking different plants/compounds that are not proven to be safe in combination, the more likely you are to eliminate bad reactions.

Great post I can see your reasoning. I know nothing of Kava pharmacodynamics so I can't comment on that. But hopefully offer some points on mistakes in the theory, please correct me if I'm wrong.
"The definition of elimination half-life is the length of time required for the concentration of a particular substance (typically a drug) to decrease to half of its starting dose in the body."
https://www.ncbi.nlm.nih.gov/books/NBK554498/
Elimination starts at T0:00, not from peak plasma levels. So the maths is off a bit.

"Generally it is considered that it takes 5.5 half-lifes for a drug to be removed from the body, in that it is considered to no longer have a clinical effect."
https://www.drugs.com/me...f-life-of-a-drug-458946/

You cant extrapolate dosages between species on mass alone, the standard calculation used is based on body surface area (BSA) this would be more accurate for some metabolic pathways than others but is probably a good starting point for researching dosages.
https://faseb.onlinelibr...ll/10.1096/fj.07-9574LSF
To convert the dose used in a mouse to a dose based on surface area for humans, multiply 10 mg/kg (MOAB lowest tested dose) by the Km factor (3) for a mouse and then divide by the Km factor (37) for a human. = 10mg/kg*3/37=0.81mg/kg
Here is an easier to read table:
https://www.researchgate...face-area_tbl1_296425784
Please also see this document, for a further breakdown, but more specifically to PART VII- Application of a safety factor:
https://www.fda.gov/media/72309/download

I've always assumed with reversible MAOI's the inhibition lasts along as 5.5x the half-lifes. So would require waiting 49.5 hours from the last dose. May need to get confirmation on this.

Using the HED of 0.81mg/kg as the highest acceptable limit based on your cited literature would require just under 3 half-lifes:
5mg/kg * 0.5^3 = 0.625mg/kg.
3 half-lifes: 9 * 3 = 27 hours.

As stated this is the lowest TESTED dose. Inhibition is a sliding scale not on/of. Inhibition may be low enough to not notice any compounded effects. It would be prudent to test the waters with low doses starting at 50 hours from the last dose. And slowly reduce the time between dosing, if required, whilst being mindful of the time limits you have fleshed out and paying attention to any symptoms that may arise.


THIS! As always do your math and then start small with dosages.

I would advise, for additional prudence, to check for potential intersections in the metabolic pathways including but not restricted to the various cytochrome P450 sub-types. It seems to me inevitible that kavalactones as lipophilic xenobiotics will be metabolised by one or more of these enzymes (not MAO), possibly along with ancillary effects on enzyme expression such as induction. Unfortunately this isn't something I know off the top of my head but I can look it up over the coming days if necessary.

If it turned out that kavalactone metabolism interacted specifically with the CYP2D6 pathway then we might see the half-life and maximum concentration of harmaline being increased in the case of competitive inhibition, or lowered if the expression of this enzyme was induced by kavalactones. This is something worth cross-checking.