I recently shared my work to a wider community on reddit, both with the intention of making this actually feel worthwhile by having more than like 20 views for what would amount to hours and hours of work and research and doing more work than I ever did for school and digging up articles done in intense feverish working trances etc I digress, but more importantly, I hoped to open myself up to suggestions for new obscure drugs to research in. These suggestions came in almost immediately, however it was one, from u/wherethewavebroke, that instantly caught my eye.
This drug was Matrine, an alkaloid from plants in the genus Sophora. The existence of Matrine elucidates all sorts of fascinating lines for further exploration and investigation. The skinny is: Matrine is an apparently hallucinogenic κ-opioid agonist, becoming another component in the growing puzzle that is this underexplored mechanism that can drive unique and fascinating hallucinatory effects. This potentially places κ-opioid agonists as a 4th category of hallucinogen alongside the traditionally known psychedelics (5-HT2A agonists), dissociatives (NMDAr antagonists), and deliriants (mAChR antagonists). For reference, the best known hallucinogenic κ-opioid agonist is Salvinorin A, the active chemical in Salvia. In my reading I also found the naturally occurring (from the same plant) analogue Allomatrine, which shows a similar pharmacological profile.
 |
| (+)-Matrine (left) and (+)-Allomatrine (right) |
Structurally, Matrine is a series of 4 conjoined, hydrogenated 6-member rings, interconnected at various angles. We will specifically be looking at the (+)-Matrine isomer. (+)-Allomatrine meanwhile, is a simple stereoisomer of (+)-Matrine.
Matrine, as stated before, is a natural alkaloid found in a variety of plants in the legume family (and some othes), though it is best known from species in the genus Sophora. Specficially the species S. alopecuroides, S. davidii, S. flavescens, S. griffithi, S. japonica, S. macrophylla, S. pachycarpa, S. subprostrata, S. toniknensis, and S. viciiflora1. Other species it has been found in include Daphniphyllum oldhami, Euchresa formosana, E. horsfeldii, Goebelia pachycarpa, Leontice albertii, and Vexibia pachycarpa1.
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| Sophora flavescens |
The best studied species is Sophora flavescens, which has been used in traditional Chinese medicine for centuries, where the ground dried root is referred to as "Kushen"2. It was traditionally used to treat eczema, dysentery, and pruritus2. Modern research suggests that Matrine may be useful in inhibiting the growth of tumors2.
Kushen, the form in which matrine was traditionally encountered, is a potent cocktail of compounds, an amalgam pulled directly from the S. flavescens root material. Several analogues of Matrine can be found in Kushen and have been studied for the analgesic properties, suggesting possible opioid activity. Some of the ones that have been studied in depth are (-)-Sophoridine, (+)-Allomatrine, and (+)-Oxysophocarpine3. Sophoridine had a patent application as an analgesic, demonstrating analgesia through an acetic acid-writhing test, though its action was not inhibited by naloxone, suggesting some activity other than opioid receptor agonism (though naloxone primarily acts on the μ-opioid receptor, it also blocks activity on the other two to some degree)4. Sophoridine was also found to be a stronger analgesic than matrine5. Oxysophocarpine meanwhile, appears to also have moderate analgesic properties in line with various thermal and chemical pain tests, and it also appeared to activate the GABAA receptor, similar to the action of many depressant drugs6.
More detailed receptor studies were done specifically on Matrine and Allomatrine, and this is where it gets interesting. After all, I'm not here to write about prospective analgesics, the context of this blog is clear. The particularly interesting effect we're homing in on is κ-opioid agonism. κ-opioid agonism often exists among a cluster of other opioid receptor effects, but certain compounds seem especially selective for the κ-opioid receptor. κ-opioid agonism in my opinion, stands to be an entirely new mechanism of action to fit under the umbrella of hallucinogenic drugs, which normally just include psychedelics, dissociatives, and deliriants. κ-opioid agonism induces a totally distinct hallucinogenic experience that sets it apart from the rest, distinguished by a physical sense of dissociation coupled with intense visual patterning like psychedelics, with the dysphoria and clear coherent hallucinations of deliriants. This mechanism of hallucinogenesis is typified and best understood through Salvinorin A, the active alkaloid in Salvia. It has also been demonstrated as the likely culprit in the hallucinogenic effects of the Benzomorphans, which can be read about here. And perhaps Matrine (and Allomatrine) could also be added to this list, pending further study.
The evidence that these compounds are κ-opioid agonists is strong. Let's see what we have before us. A study by Kamei et al. 1997 compared Matrine to Pentazocine, one of those aforementioned benzomorphans that shows broad activity across all of the opioid receptors, but particularly the κ-opioid receptor. The behavioral effects in mice in various pain tests between the two compounds was near identical, suggesting a similar mechanism of action7. To really narrow down what was going on however, a different test was performed. 3 different highly selective opioid receptor antagonists were prepared: β-Funaltrexamine (FNA), Naltrindole (NTI), and Nor-binaltorphimine (BNI). These antagonists specfically blocked action on the μ-opioid, δ-opioid, and κ-opioid receptors respectively- pretty much if these were administered with matrine and the analgesic effects disappeared, you could guess that that was a receptor matrine was normally acting on. This test showed that Matrine seemed to act primarily on the κ-opioid receptor, and to a lesser degree, the μ-opioid receptor7.
Another later study performed a similar test on matrine (yet again) and its analogue Allomatrine. This test clearly indicated the same primary κ-opioid agonist activity in Allomatrine too, though Allomatrine had seemingly no reaction to the μ-opioid antagonist8.
So if that jargon was too much, I will just say it like this: the evidence points strongly towards Matrine and Allomatrine being κ-opioid agonists. But the hallucinations you ask! It is clear looking at a list of κ-opioid agonists, there are many compounds that are clearly not hallucinogenic. Rather, we are looking for potent and highly selective κ-opioid agonists, which primarily target that receptor with little peripheral action. These show the most promise as being hallucinogenic, and this property can be seen in known hallucinogens like Salvinorin A or the Benzomorphans. Matrine and Allomatrine seem to follow this pattern, which shows promise.
But I'm not writing this piece because of potential, I'm writing this piece guided by a report from a brave redditor who had actually intentionally ingested Matrine to bring out these very effects. Of course, you should take a single data point of a single reddit report with a grain of salt but it should at the very least provide a platform for further investigation.
Some excerpts from this report by u/wherethewavebroke are as follows:9
"Prior to my trials, I could only find a single other report of usage, from /u/kpinner in a since deleted post, where they claimed to consume a full gram at once. They reported long lasting effects and visual distortions, especially CEVs."
"4 days later, at 9pm.
I mixed 250mg in with pickle juice again, although of a much better quality than last time.
This stuff is fairly bitter, but easy to wash down if you chase it with water. Similar effects to the previous experiment developed, slightly more potent, although I wouldnt say doubly so. Took a walk outside and noticed some minor visual distortions, very occasionally. It was very slight bending of things, similar to with some dissociatives. Later on, when I was back inside, I had some very persistent afterimages. After looking at the lights on my ceiling for no more than a second or two, I had remaining afterimages of them where I looked, both with eyes open and closed. They moved a tiny bit, and faded after a couple minutes. No other visual effects were noticed."
As for Allomatrine, it has a similar profile in animal trials, particularly the observation that a specific κ-opioid antagonist blocks its action. It can be reasonably presumed that Allomatrine may have similar effects to Matrine, though of course this cannot be known for sure until it is tested in humans.
The observed analgesic doses in mice (equivalent to that of pentazocine) were ~30 mg/kg subcutaneous for both Matrine and Allomatrine, though other tests indicate that Allomatrine may be more potent8. This would be a dose of 2100 mg in a 70 kg human. It should be noted that the human trial above was only a fraction of that dose, and there were no noteworthy behavioral aberrations in mice at their significantly higher dose. I really cannot safely say what the dose in humans may be, especially accounting for the different route of administration and the ways in which we may uniquely metabolize the chemical, but it appears that 250 mg is at least a safe starting point, and perhaps a lower end of a dose.
Matrine and Allomatrine are just two components of the aforementioned extract from Sophora flavescens used in traditional Chinese medicine that is referred to as "Kushen". It is still available in contemporary times as a formulation called "Compound Kushen Injection" (CKI) (which also includes extracts from the plant Rhizoma smilacis), indicated for cancer treatment. Kushen is also available in oral tablets, indicated for a range of dermatological maladies. Indeed many alkaloids from Sophora show promise in slowing tumor growth2. So could CKI be used to achieve the interesting effects of Matrine and Allomatrine?
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| Kushen Tablets sold for acne treatment |
I would say not likely- CKI is a cocktail of a huge variety of compounds, many of which have not been properly isolated and researched- their potential side effects are entirely unknown, though a selection of them seem to be analgesic or possibly opioids. The compounds included in CKI can be found in this table, taken directly from Zhou et al. 202010.
|
No. |
Compound |
|
1 |
5,6-Dehydrolupanine |
|
2 |
5α,9α-Hydroxymatrine |
|
3 |
7,11-Dehydromatrine |
|
4 |
9α-Hydroxymatrine |
|
5 |
9α-Hydroxysophocarpine |
|
6 |
Adenine |
|
7 |
Baptifoline |
|
8 |
Isomatrine |
|
9 |
Isophocarpine |
|
10 |
Lamprolobine |
|
11 |
Liriodendrin |
|
12 |
Macrozamin |
|
13 |
Matrine |
|
14 |
N-Methylcytisine |
|
15 |
Oxymatrine |
|
16 |
Oxysophocarpine |
|
17 |
Oxysophoranol |
|
18 |
Oxysophoridine |
|
19 |
Piscidic acid |
|
20 |
Sophocarpine |
|
21 |
Sophoranol |
|
22 |
Sophoridine |
|
23 |
Trifolirhizin |
It's entirely possible that other interesting κ-opioid agonists may be hiding out among these active compounds. Understandably, most research around them focuses on their potential to inhibit tumor growth, which is of course much more important than their psychoactive potential. But the possibility is out there. A number of these in fact are simple stereoisomers or close analogues of Matrine.
Furthermore, as it stands I think it may be worth lumping in κ-opioid agonists as a 4th class of formally defined hallucinogen, alongside the familiar 5-HT2A agonists (Psychedelics), NMDA antagonists (Dissociatives), and mACH antagonists (Deliriants). As it stands, this group perhaps at least warrants the inclusion of Salvinorin A, the Benzomorphans, and Matrine/Allomatrine, among many possible others that have yet to be surveyed! A qualitative characterization of consistent hallucinatory effects across all the substances with κ-opioid agonist activity must be done too, and there simply does not yet exist enough data for that across multiple compounds. This is made messier by the fact that few compounds are exclusively κ-opioid agonists- many are very non-selective and hit a variety of receptors for all sorts of effects. Nonetheless some commonalities appear to be a physical sense of dissociation or derealization, bright, patterned and vivid visuals, a lack of inherent euphoria (or even dysphoria), and vivid hallucinations that border on delirium. In sensory aspects it seems almost like the other three classes of hallucinogen rolled into one, but only further study will illuminate this picture better.
Sources and Further Reading:
2- Zhang H, Chen L, Sun X, Yang Q, Wan L, Guo C (2020) Matrine: A Promising Natural Product With Various Pharmacological Activities. Front. Pharmacol. 11:588
3- Liu XJ, Cao MA, Li WH, Shen CS, Yan SQ, Yuan CS (2010) Alkaloids from Sophora flavescens Aition. Fitoterapia 81(6):524-527.
4- Ju H (2001) Sophoridine and its application in analgesic CN1211083C
5- Zhang S, Li H, Yang,S-J.(2005). Comparison of analgesic effects between matrine and sophoridine. Journal of Jilin University(Medicine Edition) 31:561-563.
6- Xu T, Li Y, Wang H, Xu Y, Ma L, Sun T, Ma H, Yu J (2013) Oxysophocarpine induces anti-nociception and increases the expression of GABAAα1 receptors in mice. Molecular medicine reports 7(6)
7- Kamei J, Xiao P, Ohsawa M, Kubo H, Higashiyama K, Takahashi H, Li J, Nagase H, Ohmiya S (1997) Antinociceptive effects of (+)-matrine in mice. European Journal of Pharmacology. 337(2-3):223-226.
8- Xiao P, Kubo H, Ohsawa M, Higashiyama K, Nagase H, Yan YN, Li JS, Kamei J, Ohmiya S (1999) Kappa-Opioid receptor-mediated antinociceptive effects of stereoisomers and derivatives of (+)-matrine in mice. Planta Med. 65(3):230-233.
10- Zhou W, Wu J, Zhu Y, Meng Z, Liu X, Liu S, Ni M, Jia S, Zhang J, Guo S (2020) Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology. BMC Complement Med Ther. 15;20(1):6.
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