Pharmacology The unique stimulant effects of Kratom

[knockout_mice]

I've always been fascinated by the stimulant effects of Kratom, and I'm curious about the pharmacodynamics behind it. I realize that other opioids can also have a stimulant effect, especially after tolerance sets in:

• One such example is Tramadol, but the pharmacology there is pretty clear: it's also an SNRI.
• Tianeptine is a weirder example because it's a selective mu-opioid agonist. (Funnily, it was kept as a "secret" by Servier. They did a huge receptor screening and somehow forgot to test opioid receptors. Honest mistake?) It shows that a selective opioid agonist can also have a somewhat stimulating effect without other known receptor interactions.

Kratom is different, though. From my personal experience, it's a pretty powerful stimulant, but the feeling is not similar at all to classical NDRIs and catecholamine releasers. It's also very different from Tramadol.

Excerpt from "The pharmacology and toxicology of kratom: from traditional herb to drug of abuse":

Mitragynine and 7-HMG are selective and full agonists of μ-opioid subtype receptors [3, 7, 8, 21]. Mitragynine exhibit sactivity on supraspinal μ- and δ-opioid receptors causing its characteristic analgesic effects [3, 7, 8, 21]. With consideration to the interactions at the cellular level, studies suggest that neurotransmitter release from the nerve endings at the vasdeferens is inhibited [21]. This inhibition is suggested to occur through the obstruction of neuronal calcium (Ca2+) channels[7, 22].

Blocked stimulation of serotonergic 5-HT2A receptors and stimulation of postsynaptic alpha-2 adrenergic receptors are thought to contribute to stimulant activity [3, 8].Additional psychoactivity is said to exist as a consequence of binding affinities exceeding that of morphine at the δ- and κ- opioid central receptors [21]. Moreover, 7-HMG provides high opioid receptor affinity with full agonist properties [8,21]. While polarity is increased due to the additional hydroxylgroup on 7-HMG as compared to mitragynine, increased activity of 7-HMG is otherwise not well understood [21].

From "Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract":

The effect of kratom on MOR is quantitatively different to that of morphine, the affinity is less, and kratom was not able to induce a comparable phosphorylation (Fig. 9) and signal induction of MOR (GTPγS stimulation, Fig. 8). The effect of kratom is less pronounced, and in comparison to the specific μ-opioid agonists, it is about two orders of magnitude less potent. In addition to MOR binding, the extract also binds to DOR, KOR, and dopamine D1 receptors

I'm looking forward to hear your theories. Kratom might pave the way to more gentle stimulants in the future.

 

[chippermonk]

I'm fairly new to kratom and use it only at low levels, so my opinions should be taken with a grain of salt, but it is interesting how stimulating it is for me. It makes me think of how low dose oxy can be so stimulating, but it does have it's own qualities in that respect.
Just recently I tried a new batch from a vendor new to me( Wild White Jongkong, whatever that is) and holy crap was that stimulating at 2.5 g! I started wondering if it had spiked because it seemed so unlike others I have used. Too much up, personally.
One thing I have observed from my use, it always seems like I start off with a good stimulation and then that wears off after a couple hours and I'm left with a much longer lasting relaxing phase. It's like the alkaloids that cause stimulation are short acting whereas the opioid alkaloids are long lasting. To me, it really feels like two different experiences going on. This one yesterday, though, seemed all about the up and not about any relaxation.
Perhaps I'm reading too much into all this but it is interesting, it seems like a more complicated drug than some. From what I have read, it has a number of psychoactive alkaloids and I can make imagine that there could be some complicated interactions with other drugs. I guess all this is what people mean when they call it a "dirty" drug: more complicated effects and interactions (?)

 

[negrogesic]

There a few modes. Mitragynine, and some of the other alkaloids, are alpha-2 adrenergic receptor agonists, which results in NE reuptake inhibition. And like you mentioned, it has action (partial agonist) on 5-HT2A receptors, which can influence the release of other neurotransmitters.

So while those are actions are unique to kratom, pure MOR agonists have stimulating properties on their own right due to GABAergic inhibition and pro-dopaminergic effects.

 

[Pissed_and_messed]

aint the alpha-2 agonists decreasing the reuptake inhibition? while antagonists do act as stimulants?

 

[Skorpio]

Alpha 2 adrenergic receptors are on the same neuron that releases the norepinephrine onto the synapse. They act as a negative feedback sensor to measure norepinephrine levels and regulate release.

Alpha 2 agonists like clonidine or xylazine therefore stop norepinephrine release and drop blood pressure and cause sedation.

Alogs 2 antagonists like yohimbine or some of the kratom alkaloids increase norepinephrine release and cause stimulation.

This flavors that general hit of dopamine release caused by the mu opioid tickling.

 

[negrogesic]

aint the alpha-2 agonists decreasing the reuptake inhibition? while antagonists do act as stimulants?

Yeah i misspoke there, was inferring the reverse.

But kratom also acts in both capacities depending on the alkaloid, thus the stimulation and sedation.

 

[knockout_mice]

Guanfacine is an alpha 2 agonist used for ADHD. The mechanism of action is a bit surprising, especially that guanfacine has mild sedative effects as well.

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the prefrontal cortex.[43][19] These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A-adrenoceptors on dendritic spines, and are not dependent on activation of pre-synaptic α2A-adrenoceptors.[19] Cyclic adenosine monophosphate (cAMP)-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing.[43][44] In monkeys, guanfacine improves working memory, attention regulation, and behavioral inhibition, and these actions are independent of its sedative effects.[19] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.[43][19]

Guanfacine is much more selective for α2A-adrenergic receptors than clonidine, which binds to and activates not only the α2A-adrenergic receptor but also α2B- and α2C-adrenergic receptors and the imidazoline receptor.[19] It is weaker than clonidine in producing hypotension and sedation, has weaker pre-synaptic actions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasing locus coeruleus activity and norepinephrine release), and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors (as suggested by guanfacine being more potent than clonidine in enhancing prefrontal cortex-related working memory in aged monkeys).[19]

So the key here is that it's the presynaptic alpha 2 agonism which reduces norepinephrine release (which makes sense as a natural negative feedback loop: presynaptic receptors give feedback of the norepinephrine content of the synapse to the releasing side / presynapsis -> this in turn decreases norepinephrine release - while post-synaptic activation may have a "stimulating" effect on certain brain areas)

Dopamine D1 receptors might also play an important role in kratom's pharmacodynamics, feel free to chime in if you have some knowledge about it.

It's well known the white (and to a lesser extent, green) kratom strains have a more stimulating effect profile than red strains. This study though couldn't find any significant differences between the alkaloid composition between strains.
https://ncbi.nlm.nih.gov/pmc/articles/PMC10379209/

Could there be an unknown alkaloid that gives rise to the more stimulating or relaxing effect? Or some other substance which changes the metabolism of known alkaloids?

I don't envy researchers working on natural products, it's the same headfuck as food science

 

[JackARoe]

Looking over the thread again to understand better the mechanisms. The thread is a little heady... (in a good way) I will read it over a few times. Thanks all.

Total personal observation here. The stimulating effect of kratom resembles the same type of burst I get with most opioids but much lighter. I mean that same effect if laying down can put me to sleep too. It is a burst but it is not like say ephedrine or yohimbe that would keep you awake. But I see a few posts differentiating these things already above and detailing some differences.

 

[Mjäll]

I think the mild opioid effect is responsible for most of its psychoactivity including the stimulant aspect. It's fun to speculate about other receptors but it seems to get convoluted fast as the present knowledge simply doesn't allow any real conclusions.

 

[ecstacylover]

I've used 7-ho-mitragynine quite a bit, and it doesn't replicate the best aspects of kratom. Kratom has a remarkable pro-social effect. 7-ho-mitragynine feels more drug-like and more sedating, but it's a much less useful experience. It does seem that less is more with 7-ho, so perhaps I should experiment more with lower doses.

There's also evidence that 7-ho is the primary driver of kratom's MOR activity, or at the very least, its analgesic activity (which is MOR-dependent).

Accordingly, we conclude that 7-OH formed as a metabolite is sufficient to explain the opioid-mediated analgesic activity of mitragynine and that the parent compound does not make a significant contribution to its own analgesic activity in mice. ref

So I personally am skeptical that MOR agonism explains the kratom 'magic'. I also doubt that 5-HT1A agonism (I believe this is the serotonin receptor that kratom most potently effects ref), plays a role in these pro-social effects, since buspirone doesn't replicate them for me (yet at least, I've only been taking it for a couple weeks) and others, according to most of the reports I've read.

It's a nice idea that some type of adrenergic action might be at play, but most of the 'evidence' I've seen for kratom having adrenergic activity is very indirect. If anyone can find a study showing efficacy (or antagonism) of kratom alkaloids or metabolites in adrenergic receptor functional assays, please link them. I haven't seen any.

Would be nice to find a molecule which has these pro-social effects, especially without the libido issues (which I'd guess come from the MOR agonism). I've never had anything else like that which is also so functional. Plus I don't take kratom anymore cause it's horrible for skin and hair, so having a more selective pure compound would be nice.

 

[AngelsandFairiesarereal]

Plus I don't take kratom anymore cause it's horrible for skin and hair, so having a more selective pure compound would be nice.

I take kratom sometimes, but lately have been taking the 7oh tablets (7-hydroxymitragynine). Anyways, I’ve read other people here and there say things about kratom being bad for skin and hair. What do you mean by that. As a female with long hair (well I shouldn’t say that, I’m sure many males could feel the same) but, I’m nervous to take something that could be bad for my hair or skin. What did you notice about it how it affected you, if you don’t mind me asking.

 

[knockout_mice]

Regarding postsynaptic alpha-2 agonism, check out these:

• "The Adrenergic a2 Receptor-Mediated Discriminative-Stimulus Effects of Mitragynine, the Primary Alkaloid in Kratom (Mitragyna Speciosa) in Rats" (10.1096/fasebj.2020.34.s1.05233)
• "Pharmacologic and clinical assessment of kratom: An update" (10.1093/ajhp/zxz221)

Mitragynine stimulates postsynaptic alpha-2 adrenoceptors and inhibits cyclooxygenase-2 messengerRNA (mRNA) and protein expression, suggesting nonopioid receptor pain relieving effects. The alpha-2 adrenergic agonist effect can also lessen withdrawal symptoms.

> kratom being bad for skin and hair

I'm not sure about this. Skin and hair usually get worse as we age. I'm not saying this statement is false, it's just hard to verify.
Personally I'm more worried about the amount of powder required and its effect on the gastrointestinal tract. A person with tolerance can easily eat 25g a day (even with T-breaks), also because it's so short-acting.

> I've used 7-ho-mitragynine quite a bit, and it doesn't replicate the best aspects of kratom. Kratom has a remarkable pro-social effect. 7-ho-mitragynine feels more drug-like and more sedating, but it's a much less useful experience. [...] So I personally am skeptical that MOR agonism explains the kratom 'magic'.

Interesting! I don't get strong opioid effects from kratom anymore, I only get the pro-social and stimulant effects. I have experience with various potent opioids, the "warm blanket" opioid feel is basically non-existent for me now, also no miosis (pinpoint pupils). Kratom seems to be a very weak opioid.

I'm a bit wary of giving 7-ho a try, because I believe it wouldn't have the same "rate-limiting" effect as kratom. If you "overdose" on kratom, you just feel sick, intense nausea and tremor (the nausea is probably because of the amount of powder, not just the opioid effect). I think this makes raw powder very effective at limiting intake. Another symptom of taking too much is hiccups. I noticed smoking tobacco or vapes can start these hiccups while on kratom. Otherwise I basically never have hiccups.

 

[knockout_mice]

Notes:

• Corynanthine (α1-adrenergic and α2-adrenergic receptor antagonist) is very similar Mitragynine in 3d structure. Read more here
• The pro-social effects of kratom might be related to dopamine D1 activation, I need to research it further though.

 

[ecstacylover]

I take kratom sometimes, but lately have been taking the 7oh tablets (7-hydroxymitragynine). Anyways, I’ve read other people here and there say things about kratom being bad for skin and hair. What do you mean by that. As a female with long hair (well I shouldn’t say that, I’m sure many males could feel the same) but, I’m nervous to take something that could be bad for my hair or skin. What did you notice about it how it affected you, if you don’t mind me asking.

I used it daily for 3 months straight earlier this year. When comparing myself to pics I took at the beginning of the year, my face looked significantly more aged. Around the 3 month mark I also started increased shedding and I noticed that my hair was looking thinner than it had the beginning of the year.

If you go search on forums you will find tons of reports supporting this as well. I didn't even realize this was an issue until I noticed it myself, then I went looking and was like holy shit, there's tons of anecdotal reports on this. Thankfully most of the reports suggest that these effects are reversible once you stop kratom, and that's been my experience as well. People do claim that this is an issue due to heavy metals in gas station or smoke shop brands because of the lack of QC, whereas it doesn't seem to be an issue with some online vendors. That may be true (although I've seen no hard evidence) and FWIW I was using smoke shop kratom, but it's just not worth it for me to continue.

Anyways, I'm pretty tuned into my appearance, and I take things like rapamycin, tretinoin, and finasteride. as I'm very interested in the anti-aging/longevity movement. I also look young for my age, and it was pretty noticeable the changes kratom was causing to my skin and hair. This was only on 4-6g/day.

The Adrenergic a2 Receptor-Mediated Discriminative-Stimulus Effects of Mitragynine, the Primary Alkaloid in Kratom (Mitragyna Speciosa) in Rats" (10.1096/fasebj.2020.34.s1.05233)

The only thing you can reliably say from this study is that mitragynine has alpha2A and alpha2C affinity. To say anything more than that (agonist or antagonist) you would need functional assays. Drug discrimination studies are nice supporting evidence, but they're way too 'messy' as a primary means of MoA interpretation.

• "Pharmacologic and clinical assessment of kratom: An update" (10.1093/ajhp/zxz221)

You'll notice that both of their citations for the claim "Mitragynine stimulates postsynaptic alpha-2 adrenoceptors" are also reviews, rather than original research. This is the problem with many reviews for poorly understood drugs and it becomes like a game of telephone and incorrect or unsubstantiated information becomes amplified. To show that mitragynine stimulates alpha-2 adrenergic receptors you need functional assays, or some evidence that it increases norepinephrine release. Showing that it selectively stimulates postsynaptic receptors would require additional evidence on top of that.

I'm a bit wary of giving 7-ho a try, because I believe it wouldn't have the same "rate-limiting" effect as kratom. If you "overdose" on kratom, you just feel sick, intense nausea and tremor (the nausea is probably because of the amount of powder, not just the opioid effect).

Probably for the best, although I will say that 7-ho seems a lot nicer than traditional opiates. It had no withdrawal for me even after taking daily for 2 weeks (although I was still taking kratom at the time). No constipation, and very easy to curb usage.

Worth mentioning that 7-ho activates the Gq arm of MOR but antagonizes the beta_arrestin2 arm ref, which is often implicated in the negative side-effects of opiates (GI slowdown, respiratory depression, tolerance, addiction).

 

[knockout_mice]

Interesting that the hair & skin effects are so common. I didn't notice any change regarding my appearance, though people usually think I'm 10 years younger than in reality, so maybe I start from a good baseline. I'm curious what might be the cause. Hair effects may be related to testosterone (or DHT). I know opioids have a dampening effect on endocrine function (e.g. irregular periods). Negative skin effects might be because of general oxidative stress. Heavy metals would explain both.

Do we know anything about the usual contamination level of kratom products? Is there any way to remove these toxins?

> To show that mitragynine stimulates alpha-2 adrenergic receptors you need functional assays, or some evidence that it increases norepinephrine release.

I found the postsynaptic alpha 2 agonism mentioned in many papers, but I got tired of following citations after a while. It's very annoying that papers include such a claim, then reference a review paper which references another review paper... What I linked was the best I could find so far. I'll continue looking for evidence.

> Worth mentioning that 7-ho activates the Gq arm of MOR but antagonizes the beta_arrestin2 arm ref, which is often implicated in the negative side-effects of opiates (GI slowdown, respiratory depression, tolerance, addiction).

"tolerance, addiction" -> Perhaps the beta arrestin 2 arm is implicated more in addiction, but any drug causes addiction which produces euphoria or desirable effects in general. By tolerance I think you mean receptor / synapse-level adaptations. Every drug causes system-level (downstream) changes which lead to tolerance. An opioid without tolerance would be amazing though, probably the closest thing to a free meal. :- )