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Kratom and the FDA

The FDA has made an announcement about kratom, a plant preparation (Mitragyna speciosa) that (depending on who you ask) is a drug of abuse or a way for people to get off of other drugs of abuse. Specifically, it’s used as a way to mitigate opioid withdrawal symptoms, which is reason enough to wonder if it contains opioid ligands itself.

And that’s what the agency says is the case. The key part of their case, though, is not so much pharmacological as computational:

Notably, we recently conducted a novel scientific analysis using a computational model developed by agency scientists, which provided even stronger evidence of kratom compounds’ opioid properties. These kinds of models have become an advanced, common and reliable tool for understanding the behavior of drugs in the body.

Specifically, the FDA says that they’ve modeled the most common compounds found in kratom and determined that they have similar 3D pharmacophores to known opioid ligands, and they’ve done docking studies with the mu-opioid receptor, among others, that would predict potent bind constants. Now, that’s not the language the press release uses, of course – I’ve translated from the talk of “3-D computer technology” and the like. Trying to impress an experienced drug discovery researcher with talk of advanced 3-D modeling technology is futile, by the way – we’ve seen it work, we’ve seen it fail, we’ve seen several generations of the software, and we’ve seen people who know how to use it and people who flail it around like a spiked club.

So as an industrial medicinal chemist, I have some problems with the way the FDA is making its case here. It’s true that computational models of drug function have become more common, but “reliable” is a tricky word. If these things were truly reliable, to the point that you’d be comfortable setting government policy according to their results, then we folks in the drug industry wouldn’t have to physically screen so many new compounds in actual assays. But we do. Computational models can be useful, but that utility has to be checked against experiment every time to make sure that you’re on the right track, since the number of wrong tracks is basically infinite.

If you had “natural products pharmacology” as the next subject likely to make the news headlines, then, it’s time to collect your winnings. For people just coming to the subject, though, it’s important to get some background. Plants most certainly do have a lot of pharmacologically active substances in them, and these can have a huge range of effects (effects that are, as always, related to the dose of the substances themselves). There is no reason whatsoever to believe that a substance is more or less harmful because it comes from a plant or other natural source; such compounds range from vital nutrients to horrendous poisons. The only way to be sure is to study everything in detail.

What’s known about kratom and its components, then? Here’s a recent open-access paper that summarizes the situation. Kratom itself has been used for hundreds of years, at the very least, by people in the plant’s range as a mild stimulant and medicine, so it surely does have pharmacological effects. The most abundant natural product in the plant is called mitragynine, an indole alkaloid, and there are several closely related compounds as well. Among these, 7-hydroxymitragynine has received attention because (although a minor component) it may well be more pharmacologically active. As is often the case, analysis of these effects is complicated by the way the amounts of these alkaloids vary between samples – age of the plant, growing conditions and season, treatment of the harvested leaves, etc. all affect the profile. Some kratom samples, for example, don’t seem to have any of the 7-hydroxy alkaloid in them at all.

The paper referenced above finds that mitragynine is a partial agonist at the mu-opioid receptor and a competitive antagonist (micromolar affinity) at the kappa receptor. The other related alkaloids were basically inactive, except the 7-hydroxy, which is indeed a more potent, more efficacious partial agonist at mu (IC50 about 34 nM, tenfold better than mitragynine), as well as an antagonist at both kappa and (weakly) delta. The compounds are all characterized fully on the human receptors both functionally and by radioligand displacement for binding constants.

Now, that makes me wonder why the FDA is going on about their advanced modeling work on the kratom alkaloids, when there is already experimental evidence for whether they bind human opioid receptors. The agency’s press release does mention that “This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors“, and this must the some of that previously available data. Needless to say, I believe that it’s much stronger evidence than a computational model, which is a view that would be shared by molecular modelers themselves. Well-controlled experimental data are the aces in the scientific deck.

There are more interesting details about the pharmacology of these alkaloids (specifically, the pathways that they activate once the bind to the receptors), but I’ll save those details for another day. The point is that yes, kratom’s active constituents do indeed act on opioid receptors – possibly in a way that would corroborate the reports of them being useful for helping with traditional opioid withdrawal, but that remains to be put to the test under controlled conditions as well. As you’d imagine, the evidence at the moment for that use is an interesting but totally mixed-up anecdotal stew, from which it would be hazardous to draw anything actionable.

It would appear, then, the the FDA is well within its purview to regulate kratom. We’ve sort of grandfathered in the coffee and tea plants, and the pharmacology of caffeine has been well worked out by now, but if you set up a business openly selling coca leaves or khat, you can expect a visit from the authorities as well. The same goes for kratom. Calling it an “herb” is meaningless; biomedically that’s not a real category in the way that people like to use it. Strychnine is an herb.

There’s a lot of commentary running around to the effect that “You can’t patent a plant, man, so the big drug companies are coming down on kratom“. The overlap of recreational drug use with expertise in patent law is small, though. The kratom alkaloids would appear to be perfectly legitimate starting points for a medicinal chemistry program, if you’re interested in differentiating opioid receptor effects (technically, the G-protein signaling versus the beta-arrestin pathway) and if you think that has medical promise. Leaving aside the various paths to patentability that exist already, the compounds that resulted from such an effort would most certainly be patentable if they have any utility at all. It won’t be easy – the syntheses of these things are longer than we like in this business, and CNS receptor pharmacology is not easy to unravel even on a good day. It may be that the whole hypothesis here is wrong, and that the reports of kratom’s use in opioid addiction have been enhanced by a strong placebo effect. I have no idea. But with enough time and money and effort, it’s definitely possible to find out.

It’s the FDA that’s coming down on kratom, and if you think those guys are there to carry water for us in the industry, we have some rueful counterexamples to show you. No, they’re there to regulate the sale of drugs, and kratom is a drug. Maybe it’s a useful drug, maybe it’s a harmful drug of abuse, maybe it can be either one depending on the circumstances. But a drug it most certainly is.

88 comments on “Kratom and the FDA”

  1. DCRogers says:

    Should provide useful cover when the Department of Justice rolls Kratom into its campaign against marijuana, in the name of fighting the opioid epidemic.

    Where was the FDA as drug companies were shipping 20M opioid pills to a WV town of 2,900 people? https://www.wvgazettemail.com/news/health/drug-firms-shipped-m-pain-pills-to-wv-town-with/article_ef04190c-1763-5a0c-a77a-7da0ff06455b.html

    1. Isidore says:

      I think we are now at the stage where those responsible (and there are many) for the opioid crisis are trying to cover their butts but blaming someone else, usually the pharmaceutical companies. Which certainly bear responsibility, but so do the doctors who have been prescribing them like breath mints (many claiming to believe that opioids are not habit forming) and, of course, the FDA that had been asleep at the wheel.

  2. Isidore says:

    It sound like Dr. Gottlieb is more impressed with the modeling software than you, Derek. I suppose he can be excused since he is an MD and not a chemist. 😉

  3. Anonymous Researcher snaw says:

    The common OTC anti-diarrhea medication loperamide (brand name Imodium) is an opioid; it’s widely sold at drugstores and airports for traveler’s diarrhea. At the recommended dose for that indication it is quite safe. Only by taking extremely high doses can one get a noticeable “high” from it. Some people are taking such doses of loperamide. Which is dangerous.

    https://amp.livescience.com/54641-imodium-overdose-death.html

    1. fajensen says:

      Hmm, Sounds like it could suddenly be a really tricky experience to visit places like Dubai, Saudi Arabia and Malaysia if one had taken a diarrhea pill or like me carry a whole package in the toiletry bag, in case.

    2. Ryan Daly says:

      It also turns out that many people who use loperamide to get a “high” use it in combination with quinine (usually from tonic water readily available at any store) because it purportedly results in an increase in the selective permeability of the blood brain barrier to loperamide.

      1. Kyler says:

        Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier, so it can generally only antagonize muscarinic receptors in the PNS, and currently has a score of 1 on the anticholinergic cognitive burden scale. Concurrent administration of P-glycoprotein inhibitors such as quinidine POTENTIALLY allows loperamide to cross the blood–brain barrier and produce central morphine-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action. (In my experience even when it passes the BBB it gets knocked off immediatelty due to poor binding affinity.) if it did bind to the receptor for any amount of time a person would die considering the significant strength difference per weight with Morphine. Loperamide is MUCH higher.

        Loperamide has been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal were observed following abrupt discontinuation of long-term treatment of animals with loperamide.

        When originally approved for medical use in the United States, loperamide was considered a narcotic and was put into Schedule II of the Controlled Substances Act 1970. It was transferred to Schedule V on 17 July 1977 and then decontrolled as of 3 November 1982.

        I am a recovering heroin addict 10 years in that needle. Tried suboxone. Couldn’t get out of bed and wasnt sober me. As far as suboxone goes that’s a completely different topic but it was made to wean addicts. However, suboxone doctors are cash only and raise you doasage over months and years. It’s half-life makes it incredibly hard to detox from (months)

        Opiate withdrawal is horrible and I wouldn’t wish it upon my worst enemy. But Kratom saved me and continues to do so. Been sober 3 years. Own my own small business with 4 employees, have full custody of my son and if it wasn’t for Kratom I would be dead.

  4. Bryce says:

    After a surgery I became addicted to FDA approved opiate pain medication and I FINALLY pull myself out of that nightmare by drinking Kratom and now they’re trying to tell me that it’s deadly? I believe I read that acetaminophen overdose kill around 400 people in the US annually. That’s around 10x the FDA claims have been killed by Kratom. A Kratom ban is going to be a death sentence to people like me. It would be refreshing to them just admit that the pharmaceutical industry is making enough money from Kratom. Excellent article by the way!

    1. Chris Croy says:

      Calling kratom a “cure” for an addiction to prescription opiates is like calling heroin a cure for morphine addiction. How many grams of kratom are you taking per day? Have you ever tried stopping for a few days?

      1. Adam H says:

        FDA Approved prescription opiods can kill you. 2.5 -5 million estimated Kratom users in the United States and the FDA can not definitively link one single death to Kratom use. Every single death reported was either poly substance abuse or someone with previously known health issues. Your comparison of Heroin for Morphine is not logical. I quit a 120mg a day Oxycodone prescription using Kratom. I have quit using Kratom for days at a time after months and months of use. The withdrawal is similar to what I felt when I stopped drinking 6 cups of coffee a day and switched to green tea. The FDA’s announcement is simple and easily understood by everyone: If you have pain take pain killers. If you want to quit painkillers use Suboxone or Methodone because they are FDA approved drugs. The notion that FDA approval means safe is a joke.

        1. Brian says:

          I have a similar story to yours Adam. The problem we have on forums like this is that we are not scientists. The opinion of users such as us comes off as some stoner slacker talk about legalizing cannabis as we sit around and listen to Bob Marley. I own a business and have a Master’s Degree. Common sense does not always prevail. Millions of users and shoddy data that make Kratom seem dangerous can be pushed down the pipeline to create hysteria among law enforcement and a basis for scheduling. When cannabis legalization was proposed in Arizona a series of advertisements were run by a manufacturer of Fentanyl products declaring the danger a child could face if he or she accidentally consumed cannabis edibles. That’s the way it works here. “We the manufacturers of Fentanyl products wish to inform you of the dangers of cannabis!”. You don’t need a weatherman to know which way the wind blows.

        2. lsusi says:

          You said a MOUTHFUL; the FDA is a really big JOKE!

      2. Lisa says:

        Yes i was addicted to pain meds for many years and used Kratom to get totally clean. Kratom was a lifesaver to me — 1 1/2 years clean. I tapered off of Kratom and had no withdrawals whatsoever!

        1. Josh Andrews says:

          Course kraton kills pain and is not addictive
          Fancy that. And fuck the drug companies and all the people their drugs murder. Oh joy.

      3. Manna Made says:

        I’ve been drinking Kratom Tea for about 1 year. I take 2 gram doses one to twice a day. As a routine, I take a break 1-2 days every couple of weeks. I have never experienced anything uncomfortable when i don’t take it. I use it for both energy and arthritis pain. Kratom works excellent for both objectives in my case. I disagree with the FDA’s position, but I also think the FDA needs to be shut down or revamped. I have anticipated KRATOMS ban so I’ve stocked up for several years. Further I will look for ways to get KRATOM into the country, I don’t care what our corrupt hypocritical government says. I choose what I put into my body and I accept responsibility for my choices. GOVERNMENT HAS NO SAY SO OVER MY BODY. They don”t know what’s good for me, I do.

      4. Jay Schankman says:

        2-5 grams a day. I have stopped several times and felt mildly irritable for a couple days. Same as with coffee minus the headache. Next?

      5. Reginald says:

        Chris Coy you dont know what your talking about and your analogy is completely untrue. As someone who has been on prescribed pain medication for 13 years, and someone how has experienced a few months on heroin, and morphine, and someone who is now presently living a normal happy life taking kratom I know you are completely ignorant of the truth. You are someone with bad intention spreading lies that are untrue. I personally know. Prescribed opiod medications are hell, and most impossible to get off of, heroin is even harder to get off of and more dangerous. Those drugs have killed so many people around me, and sent me to the hospital several times. My life was a living hell with my mind left deprived of natural chemicals due to the effects from these drugs. Kratom literally saved my life. I am able to live a normal life now, and Im not a walking zombie. My health, and vitality are rocking. Withdraws from kratom are next to nothing compared to all those other things. People like you are the worst. Running your mouth with lies and deception. For all those in my situation we know the truth. You are an enemy and have bad intentions. Liar! I know your a liar, and me and all the people around me living a normal life can testify to that.

    2. Josh Andrews says:

      I know for a fact kratom is not addictive. It is not and never will never will. The FDA is just helping their buddies the drug companies. Sic sic sic all this is scare mongering. Remember reffermadmness.
      Don’t you people question what our government is doing. They make bank off the opioid crisis.

      1. Shulgins Ghost says:

        Kratom is absolutely addictive. Physically and mentally. No where near the level of opiates or stimulants, but it there is definitely a mild withdrawal to it and it provides a mild sense of euphoria which many find compulsive.

    3. WinterMute says:

      Kratom is a life saver! I quit pain killers and maintenance suboxone treating using Kratom. Now I can easily cycle between taking kratom and abstaining for weeks on end. Kratom gave me my life back!

  5. RigidPrinciples says:

    After having time to think about this, I hope everyone is looking at this issue broadly enough. From a principle perspective, this issue is about so much more than kratom. The question folks really need to be asking is, “In the United States, where we uniquely have inalienable, individual, inherent rights, how does any level of government believe they have the privilege to legislate what we can, or can’t, put in, or take out, of our own bodies which are our own sovereign nations?” While it is a little flattering they want to protect us, the bottom line is it is outside any government’s jurisdiction. Before We can thoroughly educate the FDA/DEA/Trump, We ourselves must understand the roots of this tyranny. The government has always known it doesn’t have the privilege to make plants illegal. They tried with the 18th amendment, but they quickly learned the 2nd amendment trumped the 18th amendment. After passing the 21st amendment in 1933, less than a year later, in knowing they did not have the privilege to make machine guns illegal, they simply perverted the 16th amendment, and passed legislation stating in order to possess a machine gun, you first needed a tax stamp from Congress, which they printed few of. This Jedi mind trickery was only possible because the People were docile after the 21st amendment. This single act set the stage for the tyranny We see today from the FDA. As in 1937, the government passed the Marihuana Tax Act, stating in order to possess marijuana, you first needed a tax stamp from Congress, where they simply didn’t print any stamps. This is the basis for how our government originally overstepped its bounds. We have to fight the tyranny at the root. We the People would never stand for that outright tyranny in 2018. Could you imagine? Sure you can exercise your 5th amendment, but first you need to possess a 5th amendment tax stamp, and sorry we aren’t printing any. Technically, via precedent, our government feels they have that privilege. Unfortunately, since the original shenanigans were in the 1930s, everyone just feels it’s always been like this, and that the government can do whatever they would like. Our government needs taught otherwise, and We the People must accept our responsibilities. Fear is the only motivator for a tyrannical government. If they’re not looking over their shoulders, then we’re not doing it right. Scared, not smug, they must be, in order for We the People to win this war of our generation. This war is more crucial than Vietnam, Iraq, Afghanistan, Syria, or North Korea. This war is on our own soil. Right in front of our eyes. In war, it is kosher for both sides to fight. What war has ever been won by a People who sit back and cross their fingers the attackers will just not be evil? Where only one side takes up arms against the other? We could try putting flowers down the barrels that will certainly be pointed at all of us when the DEA waits for the most opportune time to schedule this (my guess is DEA will schedule sometime between 2/15-2/28), and then turns millions of Americans into felons overnight. They are banking on us remaining docile. If they were truly scared, they’d back off. But with Trump being buddy buddy now with Duterte, it’s obvious he is supportive of death squads if We the People possess plants that compete with GlaxoSmithKline and the others. Life is short. There is no greater noble cause than fighting tyranny…fighting for our freedoms…being selfless in this war, for a better future for our children.

    1. Old Timer says:

      While this is a strongly worded post, there are some excellent points. I agree with Derek’s conclusions in the narrow confines of the FDA’s role, but Dr.Principles reminds us about the bigger flaws in the system. How many lives need to be ruined to satisfy bureaucratic drones operating under mindless orders created by radical conservatives? Why can’t we choose education over incarceration? Disgusting and tragic.

    2. myma says:

      Dude, you can just grow your own morning glories which are readily available and grow like weeds.

    3. me says:

      Googling any portion of your comment shows that you post it verbatim whenever an article or blog post appears relating to Kratom.

      1. RigidPrinciples says:

        Once the DEA schedules kratom I’ll tell you how I really feel 😉 Until then, why retype? Easily 100+ people have tremendously thanked me for providing the insight. Those folks then spread the insight. To win this war is to understand it first.

        1. Gordonjcp says:

          I didn’t see much insight, just a wall of text drivelling on about the US government. Maybe you ought to lay off the wacky baccy before posting?

    4. lol says:

      Dilly Dilly!

      1. xiexie says:

        Oh my god, I was hoping after superbowl I would never have to hear “dilly dilly” again.

  6. MoBio says:

    1. Kratom contains CNS-active opioids.

    2. No controlled clinical trials exist to provide FDA with evidence of clinical utility.

    3. Opioids as a class have potential for abuse

    4. Schedule 1, more or less by the letter of the law, is the right conclusion.

    That being said, using docking to ‘prove’ it binds to opioid receptors is specious.

    1. mabel says:

      The implication here is dangerous, conflating ‘drug class’ with abuse potential, to reason that a drug should be scheduled.

      Most obviously, agonist/antagonist activity matters. Naloxone, a life-saving opioid antagonist binds to mu-opioid receptors, but it’s not scheduled.

      What about tramadol? that has clinically-relevant mu-opioid activity as a mixed agonist, but it’s only schedule IV. Kratom doesn’t induce fatal respiratory depression, unlike heroin but like tramadol.

      Many people are using kratom to stave off withdrawals and wean themselves off of harder opiates. If the drug is placed into schedule I, all those people will have to choose between the black market and the rehab clinic, and many cannot afford the latter.

      Keeping kratom unscheduled may have an intrinsic medical use – preventing kratom users from going back to dope. The DEA must not schedule kratom until that policy trade-off is investigated scientifically.

      1. Peter B says:

        Despite what Jennifer Kurtz says, Kratom is indeed addictive. It’s worth remembering that heroin was marketed as a cure for morphine addiction. Kratom is used in SE Asia as a way to get off heroin and I think opium.

        It may well prove to be the starting place for some useful ways to manage opioid addiction, and does seem to have less risk of respiratory depression than other opiates and opioid; this is part of the reason why the American Botanical Council recommended against placing Kratom in Schedule I status: this would interfere with research.

        They also published a good review:
        http://cms.herbalgram.org/herbalgram/issue112/hg112-feat-kratom-med-men.html

  7. Lars says:

    @MoBio, that conclusion was tested in the case of MDMA in the mid-80’s. I’m not an American, but the Judge was clear in recommending a Schedule III placement for that compound (nobody was arguing it shouldn’t be scheduled at all). However, the Judge was equally clear that the final decision lay with the director of the DEA. Who overruled the Judge. But it doesn’t make it “more or less by the letter of the law, [] the right conclusion”.

  8. Wavefunction says:

    There is a cafe named “Kavasutra” in NYC which serves kava and kratom.

  9. John Wayne says:

    I think this all boils down to three questions:
    1. Do you want to FDA to protect you from potentially dangerous and unproven preclinical drugs?
    2. Do you want the FDA to protect you from potentially dangerous and unproven natural products (aka health supplements)?
    3. Do you think that people have the right to make potentially poor health decisions by self prescribing potentially dangerous compounds (drugs or natural products) that may have higher order negative interactions with other drugs or their lifestyle?

    At the moment the law suggests that our answers to the questions are (1) yes, (2) no, and (3) no for drugs but yes for health supplements. This has absolutely nothing to do with ‘the man’ or some sort of ‘bureaucratic overreach;’ it has to do with the odd hybrid model that exists legally. Either you want to be protected by regulations or you do not; the reason why the regulations exist is because of all of the dead people. It blows my mind that the same folks who distrust the efforts of the FDA have complete faith in an unregulated, illegal enterprise to bring them something that they take internally.

    1. Some idiot says:

      Hear hear (you got there before me…). Well said…

      Basically, the FDA is saying “look guys, looks like this stuff is not properly studied, but what evidence there is suggests that it isn’t all roses. So let’s not have anyone selling the stuff until someone does the proper legwork…”

      Does that stop someone from growing it themselves? As far as I am aware, no. Does it help stop people pushing selling the stuff? Yes. What is the freedom/free speech problem here (apart from the weight on the docking studies)?

      1. John Wayne says:

        A follow up to my posting is a childhood friend of mine died as a result of taking an illicit substance. To be more accurate, everybody in the group who took it died (3 boys). I don’t think anecdotes prove a point, but they can be a powerful warning to not be stupid.

        1. Jay S says:

          Thousands die every year from taking illicit substances. Your point, again is..?

  10. CheMystery says:

    Kratomites seemed wrapped up in conspiracy theory though (a la “You can’t patent a plant, man, so the big drug companies are coming down on kratom“. ) Of course, this FDA announcement doesn’t help assuage these fears. I really wish the pro-Kratom public would familiarize themselves with some basic pharmacology and be apprised of potential quality issues and dosing from shady sources. But what do I know, I’m just a shill for Big Pharma, maaaaaaaaaan.

    1. Thomas says:

      Kratom saved my life. I went from homeless drug addict in and out of mental institutions to saine and sober citizen because of this stuff. You obviously make us out to be ignorant morons which is obvious when you say shit like maaaannnn. More people die from acetaminophen overdose than Kratom overdose so before you make your ignorance known to all of us consider the fact that this stuff saves lives and gets people off drugs and on to living healthy normal lives. When doctors are handing out narcotics like candy but want to ban something as harmless as Kratom you have to wonder what their motive is. Conspiracy. I don’t know. But I’ve seen it change lives first hand while masses of people are dying while drug companies make huge amounts of money. Who are the real drug dealers here?

    2. Worried Partisan says:

      The problem with what you’re implying, is that there has been research put into this plant. The misinformation and scare tactics are coming from your trusted source.

      You should do a little research and learn about the issue before you start implying people are just being paranoid hippies. Kratom is a far safer and better alternative to any of the other prescription drugs. Not to mention, Methadone and the like.

      I am all for regulation and standards that should be withheld by the supplier. They should have the same standards as any other company selling on the market, but Kratom in and of itself, is not a dangerous nor a deadly plant.

      There is a reason why it’s been three years that they have been trying to shut it down and it’s hasn’t happened yet. There are plenty of lawmakers and senators that have a good head on their shoulders, that realize the good that this plant can do.

      People stuck in there old mindsets are the reason why it’s an uphill battle. “Oh the FDA says it’s heroin, it has to be a drug and anyone that is taking is a drug addict hippie.”

  11. disillusioned med chemist says:

    Derek, thank you for covering this issue, and I agree on all points. I too do not understand the purpose of the FDA’s reliance on unpublished computational models when there is already a significant body of research in cells and animals over the past 20 years, which demonstrates opioid binding and agonist activity for the kratom alkaloids. Therefore, I of course agree that mitragynine and 7-hydroxymitragynine can be call opioids, but believe this paints a rather nuanced situation with too broad a brush, especially in the midst of the current opioid crisis, where the word opioid carries a tremendous amount of negative implications. As you touch on, differences in molecular signaling make these compounds an exciting starting point to search for safer opioid analgesics and may make the parent compounds themselves far safer than most of the full agonist opioids currently available. In any case, the core issue here is that placement in Schedule I will erect a massive barrier to future research with kratom alkaloids and under such circumstances we are likely to never learn the answers about this interesting and potentially efficacious natural product. We also do not exist in a vacuum and should consider the practical implications of any prohibition in terms of public health consequences. Of course, in an ideal world no one would use this substance until controlled clinical trials were conducted to affirm or contradict its efficacy for a select medical condition; but this is not the current situation. It should be recognized that at least several 10s of thousands of Americans are consuming kratom regularly, and obvious placebo effect issues aside, claim rather profound increases in their quality of life. If we are to use largely anecdotal evidence of abuse/addiction to make public policy decisions, then I would argue that we must also consider the even greater body of anecdotal evidence suggestive of efficacy and safety in treating a number of medical conditions. Again, it is impossible to conduct a fair risk-benefit analysis when we have not quantified the risk, nor the therapeutic efficacy, work which will be effectively impossible in the United States if the compounds are placed in Schedule I.

    @MoBio Your points about accepted medical use are well taken, and it is thus hard to make a statutory argument for any option other than Schedule I or nothing. However, according to the Controlled Substances Act, one of the requirements of Schedule I is that “The drug or other substance has a high potential for abuse.” Of course, the key point here is the word “high”. The DEA and other regulatory agencies have consistently perverted this language to mean “any”. To argue that ground leaf material containing on average 1-2% of a comparatively low potency opioid mitragynine (work from Smith Kline and French in the 1970s suggests a similar potency to codeine, which I might add is sold over the counter in some European countries), has equivalent abuse liability to heroin, is quite a stretch of science and logic. Admittedly, the reality here is that we don’t have any quantification of kratom’s abuse liability since no definitive human abuse liability studies have been conducted. What we can be relatively sure of is that such studies will never be conducted if kratom is placed into Schedule I given the well-known research barriers for work with such compounds. The credibility of the current regulatory framework is further questioned by the fact that LSD and psilocybin, compounds which are only self administered by animals under very limited sets of conditions, and which no scientist could credibly argue have “high” abuse liability in the way this term is typically understood (not all use should be considered abuse), are also found in Schedule I. What is really needed is a new system for regulating psychoactive substances that is in line with modern science and not driven by mid-20th-century political ideology.

    1. tt says:

      Excellent comment! Saved me a lot of typing as I do wish there was a critical evaluation of how we treat and regulate these type of plant drugs with a stronger emphasis on what we define as a “high potential for abuse” A large number of states have already decided that marijuana doesn’t fit that category, and most certainly Kratom, psilocybin, and DMT should never be schedule I for all the aforementioned points you made. As an aside, I do enjoy the Joe Rogan podcast, but have to turn it off every time he talks about pharma as his level of ignorance is stunning, but likely reflective of the majority of the public at large. It would be great if he had Derek on the show…

    2. Lars says:

      @disillusioned med chemist: Did you read the ruling I linked to (check my name…)? Also, I would say that the consequences of a Schedule I placement are not widely known. That is why Nutt, King and Nichols wrote a paper and got it published in Nature Reviews Neuroscience detailing these problems in a transatlantic perspective. And yes, international recognition is important, it is why FDA/DEA gets away with the current practice.

      1. disillusioned med chemist says:

        @Lars Thanks for the link. I had read the largely analogous conclusions by Judge Young with regard to marijuana in 1988, but hadn’t seen the MDMA ruling. Fascinating points, which only strengthen the arguments that the statutes have been distorted beyond their intended purpose.

  12. Chris Phoenix says:

    Re the plant’s makeup depending on lots of factors: A friend of mine got a tour/explanation of a traditional-medicine plant in New Zealand, which included the interesting claim that the most effective leaves would be the ones with the most insect damage. It makes a lot of sense.

    Re a few psychoactive plants being grandfathered: Don’t forget tobacco! The lack of regulation of that plant makes it really hard to argue that the FDA has a coherent mission of preventing harm. (Yes, they’re now finally starting to notice nicotine – but they left tobacco alone until vaping provided an easier way to ingest nicotine.)

    If the FDA has a theme, it seems to be change prevention more than harm prevention. Of course, in complex systems, change is often harmful – but liberals, libertarians, optimists, and technophiles are likely to take a dim view of an organization that seems to have a default answer of “No.”

    (And we might add sugarcane (and sugar beet) to that list. Sugar certainly has physiological effects, and some of its effects are psychologically related, and some of its effects are quite harmful.)

  13. Blunderbuss says:

    Maybe Orrin Hatch can save it. The pseudoscience isle of whole foods aside, there is something to be said about exploring the complex pharmacology of mixtures of drugs and plants are probably the only accessible way for private citizens to do so. Isolate and purify does help you parse out actives, but if you take cannabis for instance the sum is greater than the parts. Pure THC is not terribly pleasant for most people, but modulated by other compounds like CBD present in the plants the side effects are not as bad. The thousands of compounds in the plant have distinct pharmacology with at least 5 GPCRs involved. Each individual of course has a distinct set of these receptors and various other unique biochemical traits. It is unsurprising that some people hate the effects of cannabis while some prefer low THC strains and others are apparently immune to the effects. Why not think of natural products like wine. What is the point of synthetic wine, even if every component was masterfully added to mimic some taste sensation, Robert Parker is immune to alcohol, your Aunt likes heavily oaked Chardonnay, while you enjoy a heady Roussillon. Who is right? Let’s have both and, not either or.

  14. Uncle Al says:

    articles(.)latimes(.)com/1992-12-16/local/me-2045_1_laguna-beach
    … Laguna Beach, CA has extensive luxurious plantings of khat trees.

    Given necessary crimes, who shall be their convenient criminals?

  15. gwern says:

    They’re trying to justify ‘high potential for abuse’, for a plant product used by hundreds of thousands of Americans (I’ve talked to some kratom sellers) at a minimum, by way of… computational modeling?

    Truly, one man’s modus ponens is another man’s modus tollens.

  16. Do Better says:

    “The overlap of recreational drug use with expertise in patent law is small, though.”

    Needlessly snarky, ignorant, and false. Recreational drug use is pervasive in the legal profession (as in essentially all corners of society), though I haven’t seen numbers for patent law broken out.

    1. Lewis Stools says:

      I can attest to the potential for life disrupting addiction and horrid withdrawal from Kratom. I bought into the “miracle” plant and innocuous as coffee argument. Admittedly, I abused this substance. I’m grateful to be rid of it. Nearly lost my family and career. There is REAL addictive potential and for long-term, daily users, there is opioid withdrawal syndrome, and much aftermath to deal with after acute withdrawal has ended. I’m no biochemist, but this is a very complex plant/drug that also seems to attenuate neurotransmitters in a fashion different from typical synthetic opioids. Each batch from each vendor is different. One can purchase high potency extracts. In some states kids purchase concoctions containing kratom at gas stations.
      All that said, it is FAR safer than heroin or many other opioids because it is essentially impossible to overdose on this substance, contract Hepatitis, etc. It is a less harmful alternative to traditional opioids for those with addiction or in pain. But lets be honest, its an addictive substance and needs to be treated with respect. The pro-kratom community (steered in large part by vendors with plenty of skin in the game financially) have shot themselves in the foot by underplaying the reality of addictions that result from the chronic use of kratom.

    2. Gordonjcp says:

      But legal expertise is not exactly pervasive among the stoner community, so it’s pretty safe to just disregard anything that stoners say as stoned drivelling, even if they are also members of the legal profession.

  17. Patent Lawyer Reader says:

    In point of fact, you CAN patent a plant.

    Asexually reproducing (or plants that can be asexually reproduced, like grapes) non-tuber plants can receive a plant patent.
    * https://www.uspto.gov/patents-getting-started/patent-basics/types-patent-applications/general-information-about-35-usc-161
    * https://www.uspto.gov/web/offices/pac/mpep/mpep-1600.html

    By contrast, new sexually reproducing plants can be protected by standard utility patents.
    * https://en.wikipedia.org/wiki/J._E._M._Ag_Supply,_Inc._v._Pioneer_Hi-Bred_International,_Inc.

    So this whole theory about plants not being patentable is just wrong across the board.

    To the extent that Kratom isn’t patentable, it isn’t because it’s a plant. It would be because it’s been in public use (or sold or offered for sale) more than a year before the patent application — whether that’s a plant, a chemical compound, or any other statutory class of patentable subject matter.

    1. Jim Mowreader says:

      Thank you, Patent Lawyer Reader. The thing I love best about the “you can’t patent a plant, man” tribe is that they’re ALSO the guys who fill the discussion boards with “how dare Monsanto patent soybean plants, man?” Uhh…you CAN patent plants you don’t like, but CANNOT patent plants you do? How, exactly, does that work?

      Seriously guys, some of the anti-“Big Whatever” people are pretty hilarious. Something tells me that if the head of the DEA were to go on television, announce that weed has been descheduled and spark up a blunt, the fine folks at ABInBev, Constellation Brands, and Pfizer are not going to sit there quaking in their boots over some guy with a 200-square-foot greenhouse who sells 50 kilos of cannabis a year.

  18. Jeff says:

    I’ve taken Kratom for about 5 years now to relive chronic pain and restless leg syndrome. I’ve tried prescription opiods before and don’t care for the “high” feeling they produce. Also, the work I do requires a clear head and prescription opiods, for me at least, negatively impact my work product. Some of the posts on here seem to intimate that Kratom users are paranoid hipsters (“maaaaaan”). I run a very successful business and play tennis competitively. The tennis at my age (51) is the reason I was taking Advil three time per day (not a very healthy option I’ve been told). Kratom works really well for me and allows me to continue living the life I deserve to live. I know that anecdotal data points aren’t very useful in proving health outcomes scientifically, but thought I would offer mine up just the same. Cheers.

  19. Magrinho says:

    So many armchair constitutional scholars weighing in here… Ugh.

    It follows that your “sovereign nation” can then get behind the wheel of a car in a narcotic daze and destroy property and kill people? Or that your “sovereign nation” can refuse to get health insurance (tryranny!) , get addicted to your substance of choice and rack up $10,000s of ER bills that the rest of society pays for?

    Sign me up!

    1. anon says:

      It does not follow that they would be able to do that legally, and they would face repercussions for those actions, same as with alcohol. We already have laws for this.

  20. docking says:

    public health aside: ligand docking results are borderline meaningless and its a sad day when docking trumps experimental evidence. But amazingly, its not the first time I’ve seen it happen!

    1. jbosch says:

      It’s way cheaper to do a computational study than actual experiments. I tend to be harsh on people trying to publish computational studies only and ask them to provide at least a single experiment to support their findings or else be rejected.

      I also wonder why MD’s get these huge NIH grants and often do mediocre basic research while PhD’s struggle to get anything.
      The system is sick and deserves to crash every now and then.
      The common knowledge that academic papers doing drug discovery are not very reproducible should be examined with relation to how many MD’s were on that publication/claim etc. I would take a guess and expect that the less MD’s on a paper the higher the reproducibility of the results are.

  21. Pete says:

    The FDA is delusional. Keep krater legal. If you ban it many people will die. Far more than what the fake 46 FDA deaths the FDA claim. People will definitely revert back to hard drugs like heroin and die from ODing. People will commit suicide from depression. Banning it will create criminals and create more problems than is solves. Kratom is a mood stimulant and most of the strains feel like coffee. The FDA and DEA are liars and have no clue.

  22. Pennpenn says:

    So wait, people are getting up in arms over the FDA investigating something that walks, swims, and quacks like an opoid? Isn’t that their job? Whether or not the specter of “Big Pharma” hangs over the stage like a half inflated Lord of Darkness, they’re still obliged to actually do the investigation. Especially if there’s any merit to the notion that people are dying.

    1. Of course says:

      Of course they’re up in arms. Wouldn’t you be if the thing you are addicted to is about to become illegal? Now you risk getting arrested to satisfy your addiction.

      1. Anonymous says:

        As if jailing people with substance use disorders helps them recover…

        1. Imaging guy says:

          I should think that imprisonment is more likely to cure addiction than rehab programs. We could do a randomized trial where some addicts who have been sentenced to jail were randomly assigned to different outside rehab programs and compare the outcomes after 2 or 3 years. Current opioid problems would have been avoided if we did randomized trials to assess whether routine opioids after minor surgery and everyday pain problems were a good idea.

          1. Mark Thorson says:

            And also beatings. We need an RCT whether beatings improve outcomes.

          2. cynical1 says:

            @imaging guy: Just an FYI coming from a former medicinal chemist who has run an outpatient substance abuse clinic with my wife for the past 4 years. You might be surprised to learn where quite a few of our opioid addicts first started taking opioids/heroin. That’s right, prison. I hope you don’t believe that the prison system is drug free. Because you would be wrong.

    2. J. Benjamin says:

      There is no merit to the notion that people are dying from kratom. This whole article is about bad science in the FDA’s report. Why assume a different section is any better?
      https://m.huffpost.com/us/entry/us_5a2060a3e4b03c44072c0b91

  23. Alen says:

    No Dr will prescribe pain meds for my cancer pain but they don’t want me to take kratom. So is it that they want me to give heroin a try?

  24. cwc says:

    What is curious to me is that the definition of “opioid” includes “effects are reversed by naloxone,” which is true for M. speciosa constituents (Watanabe showed this 20 years ago) but not mentioned in the announcement. They probably lump that under “adds to our body of evidence,” but it is still noteworthy that this is not the basis of their argument.

    I cannot find specifics on this PHASE model, but I saw a talk given by FDA computational chemists recently where they used a very rudimentary model to evaluate fentanyl derivatives. Given the amount of hype in this announcement, I hope PHASE is more robust than that one was.

  25. Lawrence says:

    In para 7, of the OP, just noting a confusing part of a line: ” and this must the some of that previously available data. “

  26. Cameron says:

    Good post, and I agree that a computational model is less than impressive evidence compared to experimental evidence.

    I’d like to see animal models assessing how readily the substance is self-reinforcing, compared to well-characterized substances like ethanol and cocaine. Then doing expression studies on upregulation/downregulation of DAT and nAChR’s in brain slices would show insight as to what degree Kratom would alter reward pathways in the brain.

  27. Josh Andrews says:

    But seriously. Kratom is not addictive. Is not.

  28. Barry says:

    Maybe the FDA is more excited by the modeling/docking than by the actual measured agonism because it wants to regulate/ban future opioids w/o the need to synthesize/characterize/test them?

  29. Wonder says:

    In fact we disrespect the knowlegde of our ancestors worlwide. Most of the herbal products we consume were approved because of their knowlegde and never went through a computer model. There are many research projects on ethnobotanical herbs justifying the use based on the current science knowlegde so who were the ones with common sense?
    Since we unfortunately live in a world wherein everything must be scientific proven I am wondering why countries such as Thailand and Malaysia where it is regulated come to a mild conclusion for kratom about safety such as “not considered as a social problem”, “no death reported” and “mild withdrawl sympthoms”
    It is expected that Thailand will allow the use and cultivating of kratom somewhere in the middle of this year and therefore this discussion is more and more a joke.

    1. Pennpenn says:

      Not sure why living in a world where everything needs to be scientifically is an unfortunate situation but hey-ho.

      Also I’m fairly sure that our ancestors would have used computational models if they’d had, y’know, computers (a product of science, huh).

      In leiu of that they probably just used experimentation with a lot of dead bodies, confirmation bias, and a healthy dose of wishful thinking, all of which we’d rather avoid (since yeah, our collective ancestors knew a lot, but they also believed a whole load of bunk which needs to be sorted through).

      1. Wonder says:

        I do agree science should not be totally ignored however it can be abused for an agenda.
        A car is not dangerous but it is the driver and for kratom it is the same.
        Is the problem of the slow killing plantbased drugs sugar in food a reason to be more carefull or is the comment of Red Maeng Da more relevant?

    2. Emjeff says:

      And most of the herbal lore from various countries is contradictory or could never pass a standard clinical trial. And, don’t get me started on the variability in these types of herbal products.

  30. Red Maeng Da says:

    Seems that there’s a conflict of interest here. So the real truth is out, and there’s absolutely no way that kratom will be banned. The top 9 scientist who are the best in the world, drafted a letter to Trump , stating that banning Kratom would cause more harm, kill more Americans, and make the opiate epidemic even worse. Call the FDA’s ethics into question. The DEA is backing down, due to the fact that the FDA can’t prove without a doubt that kratom is harmful. Stating that there’s no clinical trials on humans, a d that process could take years. The DEA is even calling BS on the FDA. The FDA director will have to sell of all his stocks from the countless companies that he’s worked for, or step down. Let’s not forget he was laid to testify for the makers of fentanyl on the saftey of the drug. Under oath he swore that it was safe, just so the drug company could sell more. He lied it seems. The company ending up pleading guilty and paid 400 million in fines. Why plead guilty if you paid for the expert to prove that your drug is safe? Because to the company lied, and he took money to testify to the drugs safety. Fast forward to today….Who testified that fentanyl is safe? Who is now saying that kratom is a killer. But has insider knowledge that, it has been patented, it’s safe, and he has a financial investment in GSK. He’s a piece of shit, and everyone who believes that kratom isn’t harmful, probably believe Hillary is innocent.

    Isn’t it suspicious that PZM21, a synthetic compound derived from Kratom leaves, has been developed by researchers while the FDA Commissioner claims that the plant is a ‘Potential Kille? Sent in a letter to Robert Patterson, acting administrator of the Drug Enforcement Agency and Kellyanne Conway, who is charged by President Trump with leading the administration’s charge against the opiate epidemic. There are major issues with the FDA’s claims, not first of which is the fact that kratom (by definition) could not be an opioid. Opioids are synthetic substances and kratom is a botanical product. Then there’s the fact that the claims of kratom’s “opiate binding properties” ignores the fact that other legal substances like coffee, dairy products and even exercise can exert opiate binding. This is part and parcel of the FDA’s attempt to misrepresent the plant and the reason former head of the National Institute of Drug Abuse and world-reknowned authority on drugs and abuse, Dr. Jack Henningfield has previously called the FDA to task on their misleading “junk science.” Just so that everyone is aware, Steve Gottlieb, M.D., who’s heading the current slanderous crusade against kratom, was previously on the board of GlaxoSmithKlein & remains heavily invested. GSK are the ones who own the patent on synthetic 7-hydroxy-mitragynine. Incredibly infuriating and scandalous information.

    Did you also know before taking over the FDA and using his position to enrich his fellow legal drug dealers, Gottlieb was a member of GlaxoSmithKline’s product investment board. And, as TFTP has previously reported GlaxoSmithKline owns a patent on a kratom alkaloid designed for the very purpose of treating pain, thereby alleviating dependency on opioids.

    One of Kratom’s alkaloids—Speciofoline—was researched decades ago by Gottlieb’s former employer and its effects have been widely studied and reported on.

    It just so happens that a patent was filed for Speciofoline on August 10, 1964. The patent claims the “alkaloid has useful pharmacodynamic activity, particularly analgetic and antitussive activity.”

    But that’s not all. Other studies—which the FDA says do not exist—have been conducted for the specific task of treating opioid dependency.

    Aside from a patent on Speciofoline, US 20100209542 A1 is an application that was entered for University Of Massachusetts Medical School, University Of Mississippi in 2010. The application specifically recognizes kratom as a treatment for opioid withdrawal. US 20100209542 A1 goes on to claim that kratom could be used to help withdrawals from other drugs as well.

    In fact, three synthetic opioids were synthesized from the alkaloids in kratom from 2008- 2016: MGM-9, MGM-15, and MGM-16.

    They were synthesized from kratom’s alkaloids Mitragynine and 7-Hydroxymitragynine: to make what is essentially patentable, pharmaceutical kratom.

    These patents are essentially useless, however, with the natural version of the plant being legal. Only through prohibition will pharmaceutical companies be able to peddle their synthetic versions which will undoubtedly be far more dangerous and more expensive than the natural version.

    What’s more, Gottlieb went on to rant and rave about the alleged deaths associated with kratom. As TFTP previously reported, a FOIA request on the cause of death for the alleged 36 deaths associated with kratom illustrated that none of them showed enough evidence to prove that they were actually caused by kratom.

    In fact, the FDA even admitted this in their report, noting, “Overall, many of the cases received could not be fully assessed because of limited information provided.”

    Now, even though they admit their data is flawed, the FDA is touting a new number of 44. Even if this number were real—which it is not—it is laughable considering the fact that FDA approved drugs kill tens of thousands of Americans every single year. FDA approved synthetic opioid drugs alone kill thousands more Americans every year than all homicides combined.

    Not only will its ban push kratom into the black market, it will create an entirely new stream of revenue for the police state. The millions of innocent people who currently use kratom will be turned into criminals — literally overnight.

    We can expect to see armed raids on cancer patients and other people treating their pain with this plant. We can expect to see asset forfeiture rise and the wholesale theft of property in the name of enforcing the FDA’s ban. More dogs, kids, and adults will undoubtedly fall victim to the police state as it carries out the will of their corporate masters — laying waste to all those in their path.

    And, all of this tyranny, prohibition, theft, and violence, will be deemed necessary — to keep you safe — in the Land of the Free.

  31. Kratom is all natural and not addictive at all. There is a campaign run by the FDA and behind that are the big pharma. How such natural leaves can kill someone? There are different types of leaves and all are not same .. means few are more stronger than others. So, instead of claiming it as an opiate, a well research needed. Sufficient time, effort and education needed to study this natural and live saving herb.

    Just like the cbd oil, the FDA is creating unnecessary fear among Kratom users. Kratom is a popular herbal treatment for both chronic pain and the withdrawal symptoms caused by addiction to opioid painkillers. The 36 deaths are not linked with Kratom alone .. other opioids are the result for that. It’s a natural herb and the effects are quite similar to coffee.

    People need to understand that there are federal laws that the DEA cannot bypass. If they do, they can expect legal challenges from the industry.
    https://redstormscientific.com/

  32. anon says:

    For topics like this, is there any way we can make the CAPTCHA require commenters to correctly define the naturalistic fallacy before posting? I can’t remember the last time I saw so much uneducated drivel in an ITP comment thread….

    1. Derek Lowe says:

      That would cut things down pretty handily. . .

      1. MagickChicken says:

        I was just noticing how many of the new posters supporting kratom varied from the usual handle styles to “Proper Name” and had a tendency to use the same vocabulary and capitalize words similarly, almost as if it’s the same person trying to pretend he/she has support.

  33. Scott says:

    You make anything Schedule 1 and it becomes politically impossible to do any research and see if it has medicinal uses. (see also marijuana)

    And I say that as someone who needs to take an awful lot of Tramadol every day to be any approximation of a functional civilized adult courtesy of a nasty L1 burst fracture 17 years ago.

  34. Gar says:

    Talk to the tribes and those who have used kratom for beneficial purposes. The tribes aren’t extinct…and nobody has died from present day usage (MAYBE if there is an allergic reaction, it could happen) But why not make things harder than they have to, right people??? OF COURSE it’s NOTHING to do with profit….the government is simply looking out for our “best interest”, and only have the “best intentions” (always heard the road to hell is paved with the best intentions)

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