Friday, February 26, 2021

How Kratom Works: The one Alkaloid Theory.

 Theory: 

All effects from Leaf come from varying the level of one alkaloid: Mitragynine. So, you should be able to get every effect from every strain simply by adjusting your dosage. Every strain is essentially just a different level of mit, and is ultimately responsible for all of the effects.  

Why do We Think That? 

Some researchers did a study of a handful of "strains" from various vendors and tested them. They found that there was no significant difference in the level of 7ohm across strains. Believing that there was inaccurate sampling because "strains" are actually just blends, I did my own study looking at various strains and drying methods from multiple vendors. 

Here's what I found: 

No significant difference in levels of 7ohm across all drying methods and strains. There was the random strain with higher levels of 7ohm. McCurdy et al. thought that it was adulteration. however, I think that it's safe to say that it's not a legitimate concern in our industry. The only notable difference was in the level of Mitragynine. The other alkaloids don't really have Psychoactive effects, and they are found in such small amounts for it to conceivably make a difference. EDIT: OF COURSE THERE ARE OTHER PHYSIOLOGICAL BENEFITS OF THE OTHER ALKALOIDS, BUT I'M SPECIFICALLY TALKING ABOUT PSYCHOACTIVE EFFECTS HERE. There have been limited studies on the other alkaloids with the exception of the anti-inflammatory Mitraphylline, which is also found in cats claw and has shown much promise in treating cancerous tumors much like CBD. leaf actually also contains a flavenoid called epicatechin also found in tea, which is also effective against cancer. Reds, which are all essentially bentuangie (dried in plastic bags in the sun), simply have low levels presumably from the oxidizing effects of the sun. I found that pure bents had levels as low as .3%. Indoor dried leaf was as high as 2.3%. this would explain why a lot of reds are perceived as "weak". They really are and they don't have this corresponding increase in 7ohm. In fact, you are simply getting an "inferior' product which has less alkaloids. But, just because it has lower levels doesn't mean it has less effects. 

Here's what we used to think: 

1)The sun caused photooxidation to occur inside the plant leaf converting the Mitragynine into 7ohm through the reaction of phytochemicals and sunlight. Why did we think that? the chemical compound 7ohm is reddish in color. oxidation turns leaf red/brown. reds have a different effect (allegedly more opioid). A study showed that the conversion took place easily inside of a petri dish just by exposing the solution to sunlight. 2) Other medicinal plant chems, like cannabinoids, have psychoactive effects which contribute to the entourage effect from synergy of multiple compounds. Why did we think that? Because there seems to be so many different effects from kratom, the logical explanation would be that it's not unlike Cannabis. However, a look at the other alkaloids reveals that it might not be the case with Kratom. 

Here's what we recently discovered through research (Mainly CNS receptor panel from McCurdy et al): 

It validated what we had suspected all along, as this one study measured (quantified) the affinities to which Mitragynine binds to various receptors in a rats brain and either agonizes or inhibits. Mitragynine seems to be single handedly responsible for all of the other psychoactive effects of Kratom minus the opioid effect: 
1) stimulation through adenosine receptore antagonism like caffeine. adenosine causes and regulates sleep. without it, you get anti-sleep aka caffeine buzz. It' s noteworthy that you can only inhibit this recptor so much, ie there's a ceiling on effects just like coffee. You can only have zero adenosine production as the max inhibition. You can't have negative adenosine in the brain. 
2) mood it is sertonergic, ie it causes your brain to release more serotonin. It is an agonist at this receptor. 3) motivation/elation dopaminergic, 
4) adrenergic the a2 receptor agonism is how clonidine works to prevent opiate w/d. unfortunately, it is also a known contributor to erectile dysfunction. interesting to note yohimbine, the chemical cousin of mitragynine (structural similarity), is an antagonist. this adrenergic agonism is presumably why it is so helpful with opioid withdrawal (aside from the obvious mu opioid agonism). Clonidine, a med used for opiate w/d works the same way. 

Very important new finding: 

Mitragynine at high concentrations blocks uptatke and effects of all opioids including heroin and morphine. Mitragynine is also a cyp3a4 inhibitor. So, there appears to be a scientific explanation for 2 clear cut effects of Kratom that trade off depending on dosage: mitragynine 7ohm All strains (varied level of MG) fall somewhere in the middle. Reds have little blocking and reported Wobbles presumably because of it's lower levels. there appears to be this precarious balance between opioid effect and opioid blocking. If you take too much, you are not going to feel the effects of 7ohm. Instead, you will feel wobbles, stim, mood, etc. This phenomenon can be seen in extract, as well as certain "strains'" (presumably indoor dried, which minimized oxidation of Mitragynine causing higher concentrations). 

What this means: 

Dosing is Key There's a sweet spot for every strain. Taking the same dose for every strain and for every effect is a mistake. Strains do not have any specific properties that would vary effects except the concentration of Mitragynine. For more stim, take more. There is a threshold of Mitragynine, where it stops the conversion of 7ohm, and even stops all opioid effects. Lower levels/concentrations (like with reds) seem to allow for more opioid effect all the way up until this threshold is reached. Smaller doses allow for less opioid blocking and more production of said enzyme. 

Here's what I think now: Wobbles are caused by Mitragynine why? 

There are no opioid effects when you have the wobbles. there is a study that calls Mitragynine the great Neuromuscular blockade. they took a leg off a rats cadaver and hooked up an electrode to the phrenic nerve to make the leg twitch. When they gave the leg enough Mitragynine they were able to get it to stop twitching. the idea is that it slows/stops nerve communication to a level where the muscles in your eyes and other parts of your body stop responding. All of the effects seem to be a result of the one alkaloid Mitragynine, which in turn converts to 7ohm from oxidation inside of our bodies specifically from the cytochrome enzyme cyp3a4. So, it's not the leaf that makes a difference, it's us and how much we take. To make things more complicated, the liver has the most of this enzyme and is also responsible for metabolizing drugs from our system. So, as mitragynine is cleared out of our bloodstream, some of it (estimated 6% by recent study) is being converted to 7ohm and being put back into our bloodstream. Then, as this enzyme is used up for the conversion, or inhibited by Mitragynine, it slows the rate at which drugs are removed from the body. This means that drugs will stay inside your system for a longer time, and possibly build. Most opiate potentiators, like grapefruit juice are cyp3a4 inhibitors. St John's wort is an example of an inducer. It makes sense to me that if you want more opioid effect that you would want more of that enzyme. 

There seem to be a lot of different effects from Kratom. So, naturally it's believable that there are different types, or "strains". One would think that it's not unlike the Cannabis Industry where there has been extensive and complex breeding practices and the complex chemical profiles vary by genetic varietal: phenotypes. We know that Indonesians are not growing different strains of the leaf. It's not that they don't exist, but moot since they are not differentiating it. Even if there were different strains, the only chemical that seems to matter is the one. 7ohm is the opioid alkaloid and it's created by our bodies. Researchers have scored it on par with Morphine in it's Mu Opioid value (some as strong as 14 times the value). 

What's the significance of Mu Opioid recpetor? 

We don't know exactly. We do know that it's the same receptor that opiates like morphine and heroin hit and seems to be responsible for the perception of sedation, analgesia, and euphoria. It's interesing to note that mu opioid activity using beta arrestin pathways caused hyperactivity in rats. There appears to be somewhat of a stim effect by inducing mor, similar to inducing serotonin. Also, interesting is the kappa opioid receptor has been linked to hallucinations and other psychedelic effects like Salvia, and Ketamine. Kratom is known to effect delta and mu. Kappa is known to effect dopamine and serotonin. 

BOTTOM LINE: All effects from Kratom are dependent on the dose of this one alkaloid. If you're not feeling the opioid effects, you could be taking too much and blocking it. Why do we think that? Because 7ohm uses G protein instead of Beta arrestin to signal mu opioid receptors, there is much less tolerance, w/d, and side effects. It would take an enormous amount to build tolerance to a point where there is zero effect. At this point, it should be obvious (eye muscle problems, stim, no opioid effect). Then, because you don't feel it, you chalk it up to tolerance and take even more. Leaf is complicated, but in more ways than can be explained by the strain/vein color paradigm. 

Asians don't have problems wtih addiction because 
a) mitragynine is not addicting (rats don't come back for more) 
b) they take larger doses than we do. 

In fact, the main reason they use it is for it's stimulating properties. Chris McCurdy, the leading expert, surmised that addiction, was due to what's considered "inferior" product, or leaf that has lower concentrations of Mitragynine. It is interesting to note that the Thai/malaysians do not have bentuangie (red). Americans, on the other hand are experiencing w/d, addiction, etc...The main reason we take it is for the Opioid effect according to the largest survey in history. So, it may be the case that you need to take less for more opioid effect and more for stim. This indicates that there is probably a sweet spot for every strain and what that is depends on what the concentration of Mitragynine is in the leaf, eg you can take a lot of a red before wobbles. to get more effect, take more up until you start getting the effect blocked, at which point it will be more stim (mitragnine effect). At a particular set dose, you can categorize "strains" as being fast or slow. or, you can just adjust your dosage. Theoretically, it should all have the same effect. 

The 2 faces of Kratom: Mitragynine and 7ohm. These appear to be the main 2 that synergize. Psychostimulant and Opioid. All strains fall somewhere between these 2. 

EDIT: make no mistake about it, kratom has addiction potential despite having this limiting factor. In fact, it happens quite a bit. It def makes it harder to abuse, I think. There's this miraculous, natural regulating effect of Mitragynine that prevents overdose on 7ohm. What a combo, right? I hear a lot of people claim that they stopped using because it stopped having opioid effect on them. According to science, tolerance shouldn't build like it does with opiates. It seems hard to build, personally. I've rarely been constipated. In fact, the evidence suggests that addiction (dependence anyway) may be more likely to occur with moderate use. Let me clarify: I really think it has something to do with the concentration of one dose. one phenomenon that I can't explain is why I can't get 7ohm effects from 45% mit extract. Others claim no effect. I feel the stim, i think. How it feels to me is that when you have the wobbles, it lowers your tolerance to 7ohm while minimizing your opioid w/d from adrenergic agonism. Taking higher concentrations like extract might actually lower your tolerance to 7ohm. 

Who gets 7ohm effects from extract? Anyone? The latest survey of Americans from Johns hopkins found kratom addiction to happen to 1 in 5 users. 20% is no joke. Keep in mind that this is self reported and denial happens to be a telltale symptom of addiction making the results inherently skewed. At some point I think that you can get to a habit of use despite harmful consequences. i know a lot of people that would argue that there are no harmful consequences, ie no side effects, so no such thing as addiction. Or, addiction to the level of say a cup of coffee. But, it's apparent now, that the prevalence of addiction is twice as high as it was in thailand. I have been testing the threshold of withdrawal/dependence on myself and may start another thread to discuss it. My main issue with Kratom dependence is Sleep. I know people who wake from their sleep covered in sweat. The problem is that withdrawal, while not that severe for most, comes pretty quick for all. I'm going off on a tangent here. More on this later.

The applications of use of kratom for the opiate epidemic are huge. Getting people on Kratom will prevent overdose deaths. It's like a natural Naloxone. The question is can it reverse the opioids in your system already, ie can you give it to someone who is overdosing to snap them out of it? I think that if you are a regular user of opiates, you need to know about the existence of kratom.

STRAINS: 
Every blend results in a different mitragynine level and this is what causes the variance in effects. It's essentially this battle that takes place inside of our bodies that determines which effect will be dominant. It seems to be a precarious balance. The method of taking the same amount of every strain is a mistake. I feel like there is a sweet spot for every strain that is determined by this level of mit as well as the enzymatic processes in our body. I still can't get 7ohm effects from extract, no matter the dose. So, there remains a phenomenon unexplainable by out theory. 

eg 
bali is a 50/50 red/green blend. If we start with a 2.1% green leaf, which is what would be expected if it was dried in the shade, and then use a red bentuangie with a .33, we have (2.1+.33)/2= 1.2. What exactly is the best level for 7ohm effect is debatable. I took a poll and people reported anywhere between .8 to 1.8. as the most opioid strain. with all of the testing going on now, we should be able to narrow this down a little more. Of course, there's the variable that we may not know of yet also. 

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