Is it a good idea to make a 7-hydroxymitragynine based drug?

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A Vancouver drug company announced that it has filed a patent for a deuterated form of 7-hydroxymitragynine (7-HMG) called D7-h. The company, Nirvana Life Sciences Inc., intends to pursue D7-h as a pain relieving drug, citing 7-HMG’s partial opioid agonism, and the deuteration process that they say makes the drug last longer.

A deuterated drug is a small molecule medicinal product in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by its heavier stable isotope deuterium. Because of the kinetic isotope effect, deuterium-containing drugs may have significantly lower rates of metabolism, and hence a longer half-life

(Nirvana Life Sciences, 2022)

7-HMG is a metabolite of the mitragynine, the most abundant alkaloid in kratom. 7-HMG is a very powerful opioid on its own, but occurs only in trace to undetectable amounts in kratom. Dr. Christopher McCurdy, a medicinal chemist at University of Florida, explained the way these alkaloids work on Kratom Science Podcast #69:

I totally feel like it’s a symphony orchestra. You take 7-hydroxy out of the mix, even the amount that would be generated as a metabolite in our bodies from mitragynine, and you listen to it on full blast by itself, it’s comparable to full opioid agonists like morphine, like fentanyl. It’s something that the whole kratom community should be very cognizant of, because those are the things that are going to cause problems moving forward.

The evidence of this statement has been borne out by research. A study on kratom’s abuse liability demonstrated rats will self-administer isolated 7-HMG but not isolated mitragynine, suggesting 7-HMG has abuse potential while mitragynine does not (Hemby et al, 2019). Mitragynine has been shown to have a complex affinity for opioid and adrenergic receptors, while 7-HMG is much more selective of opioid receptors and higher binding affinity at opioid receptors (Obeng et al., 2021). Another study on nematodes found “7-hydroxymitragynine, but not mitragynine, presented with toxic and developmental effects at very high concentrations” (Hughes et al, 2022).

Furthermore, a University of Florida study found mitragynine does not rely on its metabolism into 7-HMG for its pain relieving effects, as previously thought (Berthold et al., 2021).

Mitragynine alone has other benefits. University of Florida pharmacokineticist Dr. Abhisheak Sharma told Kratom Science that “the mitragynine itself is a combination of four drugs given for receptor binding and receptor occupancy, which you need to treat opioid withdrawal. And that is the reward that this molecule has. It’s like you’ve mixed four drugs in a treatment therapy to treat opioid dependence and you can get the same thing with one mitragynine molecule.”

Given mitragynine’s benefits, and lower abuse liability as a potential pain reliever, why should a semi-synthetic drug based on 7-HMG be developed at all, given the apparent risks?

I emailed Dr. McCurdy to ask him about the science behind deuterated 7-HMG. This is his reply via email:

As far as I can tell there has been no science around this product shared in the scientific or patent literature. The hydroxy of 7-OH is known not to be necessary for affinity and it is a shape issue that is imparted to the overall structure that makes 7-OH fit in opioid receptors with great affinity and selectivity. Replacing the OH with a Deuterium would afford the same shape change and allow for patent protection and possible better metabolic stability but there is no data to base that statement on that I’m aware of. It will be interesting to see how it develops as data is made available.

A deuterated form of mitragynine has already been patented by another drug company called Kures Inc.* A clinical trial for this product is set to be completed by October 2022 (“A Study to Evaluate,” 2021).

Under current law, isolated alkaloids of plants cannot be patented (Babin, 2017). Therefore, a process like deuteration, that changes the compound from its natural form, is necessary. Whether or not this changes the effect, efficacy, or safety of the natural compound is unknown as the science behind D-7h and KUR-101 is yet to be published.

***UPDATE 10/18/2022 Response from Nirvana Life Sciences co-founder and lead chemist Robert August. This was originally posted as a comment on my LinkedIn post about the press release: https://www.linkedin.com/feed/update/urn:li:activity:6979105836220432384/

“Preclinical data has shown that by using a combination of mitragynine, 7-hydroxymitragynine, Speciogynine and Paynantheine can substantially lower cravings for alcohol in humans with alcohol use disorder with 7-hydroxymitragynine being the most significant part of the formulation. There is also data that shows promise for clinical applications for the 7-hydroxy variants of Speciogynine and Paynantheine along with other kratom alkaloids. This is only one of many reasons why Nirvana Life Sciences is working with 7-hydroxymitragynine and other 7-hydroxy compounds.

There is little research done on deuteriated 7-hydroxymitragynine and D-7h, which is an analog of the previous compound. Because of this, we are doing extensive research and in vivo and in vitro testing to better understand these compounds and their pharmacology including pharmacodynamics and pharmacokinetics.

There is little to no chance of our alkaloids making into the hands of the public because we do not sell compounds to the public. Our compounds are used specifically for clinical research and for therapy by a licensed professionals.

Nirvana Life Sciences Inc.’s work with kratom alkaloids like mitragynine and deuterated 7-hydroxymitragynine, along with various semi-synthetic and ring substituted compounds with a similar structure, is strictly for research purposes only. Our main goal is to better understand the pharmacology of the various alkaloids found in mitragyna speciosa foliage, in order to fill the gap that currently exists in the present body of research. This includes the metabolism, efficacy, neurotransmitter activity, and safety etc. of these compounds for clinical use and how the kinetic isotope effect alters the pharmacology of these compounds.

I understand that… 7-hydroxymitragynine is not novel. Which is why, as the press release states, we created a compound that is a deuterated analogue of 7-hydroxymitragynine, which is the backbone for the various semi-synthetic compounds at the heart of this patent document. Until the patent has been granted, however, the specifics of the document’s content remains private in order to protect proprietary information.

The main focus of research at Nirvana Life Sciences is harm reduction and safety, in conjunction with novel drug formulation and a better understanding of the pharmacokinetics and pharmacodynamics of psychedelic and other active compounds. This includes safer alternatives to full opioid agonist pharmaceuticals. We ARE NOT an online research chemicals (RC) vendor or a “legal highs” distribution company that sells various individual psychoactive compounds labeled “not for human consumption” yet sells them to human consumers with minimal accountability for their end use and safety simply to generate revenue. Since our products are formulated for medical research and clinical use only, there is little to no chance of our D7-h or other API’s ending up in the hands of the public at large. We are a research company striving to expand upon our knowledge of novel and rare compound formulations in order to create new and safer pharmaceuticals.

If you examine Nirvana Life Sciences history of Press Releases, you will see that we are research oriented. We perform in vitro and in vivo studies to better understand both naturally derived and synthetically created active compounds for their use in addictions management and chronic pain relief. Which is precisely what we are doing with D7-h. The reason for creating a deuterated substitution of an active compound is for use in deuterium metabolic imaging, in which metabolic pathways can be traced within the body and brain. This is not for recreational use. In fact, our company securing this patent precludes recreational based companies from using this compound to gain revenue through unsafe distribution.

I specialize in the chemistry of semi-synthetic novel compounds. As lead chemist and head of innovation for Nirvana Life Sciences, I study compounds found in nature and perform research into how altering these compounds can change both effects and pharmacology. I do this so that my team and I can create more efficient and safer pharmaceuticals. Anyway… I hope that this post has answered all of the questions presented in the OP and subsequent replies, and has helped to illuminate any misunderstandings surrounding our work with 7-hydroxymitragynine.

Thanks for your interest in Nirvana Life Sciences D-7h. Should you have any additional questions, please contact my assistant Carly at [email protected]“

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