Kratom Tolerance

Posted on January 26, 2011 by

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Intro & disclaimer
Writing about kratom tolerance is tricky, besides the fact that it is a very complex issue, a lot of factors that influence tolerance are simply unknown, controversial or not properly studied. Nevertheless tolerance is an issue that most long time kratom users encounter, sooner or later. So here we go, but please do understand that this article itself is no guideline, advice or anything else, just a combination of observations, quotes and hopefully some useful tips.

So what is tolerance to kratom?
First to understand kratom tolerance, we need to take a closer look at the inner part of our brain. Some of the kratom alkaloids, or better the metabolites, are absorbed from your blood into the brain, they cross the so called blood-brain-barrier. Once in the brain these kratom metabolites meet the brain receptors, more specifically the opioid receptors,  like the delta and Mu receptors, with who they interact.

The kratom alkaloids and metabolites, especially the 7-hydroxymitragynine and Mitragynine, fit well in the receptors. Once the receptors interact, they send of  a “signal” to the rest of the body.  These signals result in a state of analagesia, cause antidepressant effects as well as physical dependance, which are triggered by the delta receptors and the MU receptors. The later also handle feelings of euphoria and are responsible for respiratory depression.  Part of these substances act as a full agonist, or a compound that will bind to a receptor to form a complex which elicits a response, peculiar to the nature of the receptor involved.

If these metabolites of the kratom alkaloids become present in the brain in higher levels than usual, by regular usage of kratom, the brain will adjusts. The receptors for the neurotransmitters will become less sensitive or are being turned off, this is called ‘down-regulation‘ of the receptor.  Even when the same quantity of kratom is used, the brain has less (active) MU and Delta receptors that can interact with kratom metabolites, therefore  resulting in less “signals” and thus less psychoactive effects, tolerance.

The body may however also react in another way to regulate the effects of the kratom intake. For example, enzymes are produced in the body to break down  kratom. Once taken regularly,  the body can increase the production of those enzymes, to make sure that more of the kratom is being broken down faster. Since this will result in less metabolites available to interact with the receptors, it will again produce less effects.

Both these processes result in what is called the tolerance to kratom. Depending on the person, amount taken, frequency and even the various strains or kinds of kratom, these processes start to occur in weeks or months after using kratom regularly. It is important to take note that there are very different reports on the build up of tolerance,  for some this process starts soon for others later.

The dangers of tolerance
Some moderate users of natural and standard powder claim to have build no tolerance, even after frequent usage for long periods of time. Others will notice the first signs tolerance within months. As a result some are increasing the daily amount of kratom used. The latter can result in a negative spiral, whereby the user is not only using excessive amounts of kratom, but building a physical depence next to a high tolerance as well. Since the long term effects of excessive usage are not yet well understood, this should be avoided, it may well cause permanent tolerance issues or worse.

Although no scientific reseach is being done in this area, there are individual cases of users that seem to have build some kind of permanent tolerance. Possibly due to excessive kratom usage for longer time, in combination with other medications. The brain has adjusted in such a way that either the amount of receptors or the sensitivity of the receptors itself have become permantly adjusted. So regardless of the amount of kratom used, the effects are weak, even though he/she has not been using kratom for months.

Tolerance and kratom leaves vs kratom extracts
Another important observation is that kratom extracts, containing a relatively higher percentage of 7-hydroxymitragynine and Mitragynine, may lead to a quicker development of tolerance then the regular kratom powder. Users on various forums are reporting this as well and we believe that this risk is real.

The theory behind this idea is that the whole leaf kratom product contains more different kinds of alkaloids compared to the extracts. Some of the kratom leaf alkaloids like, 9-hydroxycorynantheidine and Corynantheidine, act as like antagonist. A compound that will bind to a receptor to form a complex which does not give rise to any response, so its acts as if the receptor were unoccupied.  Simply said, these minor alkaloids will not trigger any response, so the brain will not adjust. These antagonist just occupy a receptor which otherwise would have been occupied by the agonist.

So when a whole leaf product is taken the effects are more balanced, causing only a partical adjustment from the brain, compared to a must stronger adjustment or down-regulation of the receptors when only a limited set of alkaoids is consumed, as with extracts.

Resetting Tolerance
In normal situations, not taking kratom will cause the brain to re-adjust back to the previous state, this can be achieved in days, sometimes in a week.  Depending on the time that kratom had been used, this resetting may cause so called withdrawal sympthoms, which are caused by the phycisal dependency to kratom of the brain.

Days off
Taking “days off” is probably one the most effective way to deal with tolerance, next to stop taking it of course. Some claim you can take kratom only once a week for this reason, others seem to deal with tolerance by just taking one day off per week. In any case, trying to taper your kratom usage, by either lessening the frequency or the dosage used, will have a positive and direct effect on your tolerance. Receptors are given time to re-adjust.

But there are other options as well.

Stem and Vein
As mentioned before when dealing with the differences between extract and whole leaf powder, we already noticed that certain alkaloids can act in helping to reset the receptors. The partial mu-opioid agonist 9-hydroxycorynantheidine and a mu-opioid antagonist Corynantheidine are believed to lessen de brains “down-regulation” or at least slowing this down. These alkaloids appear in the leaf powder, but their numbers are higher in the stem and vein material of the leaf.

For this reason some users use the stem and vein material to “reset” their tolerance. It is reported that 2 to 3 days of extra stem and vein can help the user to achieve a much lower starting dosage of kratom. I recommend reading about this in more detail on a forum like kratomconnoisseurs.com if interested.

Switching between powders
By regular usage of a single kratom strain or powder, the tolerance can build up more quickly. I noticed someone calling this the Single Strain Syndrome. Again this is certainly not true for all users. A possible cause may be the slightly different alkaloids profiles, or number of each alkaloid,  per type of kratom. It is thought that each kratom alkaloid profile may have different affinities for the various mu receptor subtypes.  Tolerance may develop separately at each mu receptor subtype in response to a particular alkalpoid profile or type of kratom powder, When the user switches from one powder to another, the “new” kratom powder may have a different selectivity for the individual mu receptor subtypes, which may offer a way to overcome tolerance, temporarily.

General Health; Exercise and diet.
Anecdotal effidence suggests that users who have a balanced diet, which includes a variety of vegatables, have less issues in resetting the receptors. One ingredient of most vegatables, Magnesium seems to play a role in this process. When taken to a test, users who took supplements of Magnesium Citrate (available OTC) noticed less tolerance and stronger effects with the same amount of kratom taken. Although possibly effective, regular intake of Magnesium seems to decrease the effects of this “trick” a bit.

In General a well balanced diet seems to help in either overcoming quick down-regulation or in restoring the receptors more quickly to the original state. Physical exercise or sports seem to work in a similar way, a healthy dosage of daily movements tend to work for some to keep tolerance in control. Not surprisingly maybe, but important to know, those that treat their body well, seem to have less trouble with adjusting and tolerance.

Enzymes Inhibitor
As mentioned before, enzymes are produced in the body to break down the active kratom molecules. An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. So when the production of those enzymes is limited or the activity is decreased, the effects of the kratom will become stronger or prolonged, since the kratom is broken down slower. One enzyme, the cytochrome P450, or CYP3A4, is responsible for approximately 60% of metabolism of all drugs, including kratom, so this enzyme in particular is important with respect to the action, duration, and disposition of kratom and the metabolites.

Quercetin (a plant-derived flavonoid found in fruits, vegetables, leaves and grains), Quinine (Tonic) Grapeseed extract, St. John’s wort, ginseng, silymarin and kava-kava are examples of effective enzyme inhibitors that can enhance the effects of kratom, by slowing down or inducing the metabolism. A user will have good results with less kratom, so it helps in a way to taper of kratom.

Other herbal and supplemental tolerance aids.
Besides the previously mentioned kratom stem and vein, other herbal aids have said to have good effects in resetting tolerance.  Cats Claw, is another aid, since it works as an antagonists.  Phenibut is reported to be a good alternative but there are more, which will be added later.

Cross tolerance
The way opioids, like kratom, interact with the mu receptor subtypes and their ability to activate the other opioid receptor types could explain  different tolerance build up of one opioid compared with another.  In rat experiments for example, pretreatment with levorphanol caused tolerance to morphine and levorphanol, but pretreatment with morphine caused tolerance only to morphine and not to levorphanol, indicating that receptor selectivity influences tolerance.

The same kind of differences are reported by users of  hydrocodone, oxycodone,  subs etc, but there is not enough research done in this area and user reports are sometimes contradicting one another. It may well be that the ability of substances like methadone, that differentially activate delta opioid receptors, do not cause cross-tolerance for users who had become tolerant to mu opioids such as kratom and vise versa. But more research is needed to confirm this.

Enjoy kratom, but do it responsible
Concluding I just wanted to add a little note to those enjoying kratom as much as I do.  Issues of tolerance build up are often neglected and noticed when the amounts used have at least doubled to what they used to be. To enjoy this magical herb it is important to stay in control of your habit and adopt a usage pattern that fits your needs without losing the freedom to stop whenever you want.
Especially in the case of kratom, less is more and more is too often less!
Enjoy.

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Posted in: Kratom Addiction