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The Tramadol Wars

You may recall the report of the synthetic analgesic tramadol as a natural product from Cameroon, and the subsequent report that it was nothing of the kind. (That’s the paper that brought the surprising news that local farmers were feeding the drug to their cows). Now the first group (a team from Nantes, Lodz, and Grenoble) is back with a rebuttal.
They note that previous report, but also say that tramadol has been isolated from samples in a bioreserve, where human cattle grazing is prohibited. The rest of the paper goes on to analyze isolated tramadol samples by NMR, looking for variations in the 13C levels to try to come up with a biosynthetic pathway. Isotopic distribution is the way to do that, for sure – the various synthetic steps used to make a compound (and its precursors) can be subject to kinetic isotope effects, and over time, these can build up to recognizable signatures. An example of this is the identification of endogenous human testosterone versus the plant-derived material found in supplements.
The authors go over how the various structural features found in tramadol have also been noted in other natural products, and propose some biosynthetic pathways based on these and on the observed 13C ratios (which they report do vary from synthetic samples). Probably the strongest evidence is from the methyl groups, which show evidence of having been delivered by something like S-adenosylmethionine. Overall oxygen isotope ratios are also apparently quite different than commercial samples.
So the battle is joined! The confounding factors I can think of, off the top of my head, are possible differences in the synthetic routes (and thus isotope ratios) of the commercial material used here (from Sigma-Aldrich) and the material available in Cameroon. But then, the authors state here that their samples were obtained from a part of the nature reserve where people are not farming cattle. None of us are exactly in a position to judge that – I’m not going to the boonies of Cameroon to find out – but if they’re right about that, it’s also a good argument in their favor.
But the only way to really resolve this is to grow some African peach trees, feed them labeled precursors, and see if strongly labeled tramadol comes out the other end. This paper says that such an experiment is “not currently feasible”, but I have to wonder if there’s an arboretum somewhere that has such trees in it (and if such trees produce tramadol already). There will surely be another chapter to this story – or two, or three.

15 comments on “The Tramadol Wars”

  1. Curt F. says:

    Nice summary (as usual) Derek. The new paper is very interesting, and a bit surprising since I was pretty convinced by the Angewandte report that the tramadol was probably coming from the farmers (or their cows).
    Now I’m not sure what to believe. The new paper is suggestive but not quite conclusive to me. In particular, I would like to see them have plotted the data for synthetic tramadol in Figure 1, preferably for several different batches of tramadol. (In the paper, as far as I could tell, they only tested one commecial sample.) Also, the line of argumentation the paper’s text takes is “*if* it is a natural product, then our data shows it is probably via *this* pathway…” At many points, evidence supporting the idea that it *is* a natural product are mentioned, but the paper never argues cleanly against the idea that it isn’t. So yeah, suggestive but not conclusive, at least to me.
    I’m not an NMR guy, so I don’t know how easy or hard it is to do the position-specific 13C isotope ratio analysis at natural 13C abundance, but if it isn’t too hard, I can think of lots of other fun things to do with the technique. It could make it way easier and cheaper to do flux measurements in cell cultures or in vivo, because you’d only need to add in relatively small amounts of tracer to see signal, for example.

  2. Rhenium says:

    When I was home in Australia recently, my Mum pointed out a small national park. Apparently a local farmer likes to graze his cows and calves in there which is illegal. He is happy to take the occasional fine (a few hundred dollars) every few years, for the much larger dollar amount the free grass would normally cost.

  3. Mark Thorson says:

    To believe the cattle story, a) tramadol must be dirt cheap in Cameroon so the farmers can afford it, b) the cattle are dosed near the limit of what they can take, and c) the trees have some mighty biocentrating powers. Bear in mind the report was that tramadol is more than 1% dry weight of the root bark. I just can’t buy the notion that level can be absorbed from soil contaminated with cattle urine.

  4. DN says:

    Put a clear plastic bag over a tree for a day and add fully-C-13-enriched CO2. Spray water on the outside to keep the tree from cooking. Give it a few weeks to metabolize. Take samples. The mass spec results will be definitive.

  5. Algirdas says:

    @ Mark #3:
    Answers to your questions from Angewandte paper arguing against “natural product” tramadol:
    *****************************************
    The contrast in the results obtained from plants sampled from the Far North and southern regions of Cameroon along with the negative results from endophytes prompted us to hypothesize that the variable amounts of tramadol detected in selected N. latifolia roots might in fact be an anthropogenic contamination by synthetic tramadol. We conducted a series of interviews with farmers and local inhabitants at our collection sites. As a result, the following information could be gathered:
    1) An extensive off-label use of synthetic tramadol both by the farmers as well as their farm animals occurs only in the Far North region (Houdouvou). The farmers, who have to work throughout the day under the sun in extremely high temperatures, buy tramadol from the local market or from
    local street sellers (twelve pills cost less than one Euro). They consume around two to three pills, which is much higher than the daily recommended dosage, with their morning cup of tea. They report that this allows them to work all day without feeling tired.
    2) Tramadol is further fed to cattle (but not to goats and sheep) as capsules when working them in their farms (as draft animals) so that the animals do not get tired quickly. As a consequence of the high day temperatures and the strong sun, the farm animals often choose the shade of trees to relax
    and also excrete their urine and feces.
    3) Tramadol is also administered to horses prior to horse racing and is given only on the day of the competition. Generally around five capsules of tramadol (100 mg each) are mixed with flour and water to prepare a small cake, which is then fed to the horses before the race. Then, at the end of the day, the horses are “detoxified” by being fed milk.
    4) In the southern region (Bafia), the use of tramadol is not known to farmers.
    ***************************************************
    Read the entire thing (Angew. Chem. Int. Ed. 2014, 53, 12073 – 12076) – it is fascinating. To me it seemed to make a very convincing case that tramadol is an anthropogenic contaminant. I have not yet checked this latest PNAS paper to see if the rebuttal is persuasive.

  6. Morten G says:

    @5 Seems more likely that the tramadol would be coming from the farmers rather than the cows, no?
    Some plant biosynthesis would be necessary though since I assume that the active O-desmethyltramadol is secreted, right?

  7. Morten G says:

    Oh, a quick look through Wikipedia shows that the liver also strips methyls off of the N.
    “Metabolites[edit]
    O-DSMT is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP2D6. The inactive tramadol metabolite N-desmethyltramadol is also metabolized into the active metabolite N,O-didesmethyltramadol by the same enzyme.”
    It’d be kinda of fun if both groups turn out to be right. Precursor is peed on trees and the trees stick methyls back on and store the tramadol.

  8. Mark Thorson says:

    If the notion is that the farmers are urinating on the root bark, then the scientists come along and take samples of the root bark, that seems plausible. That could result in the high level reported. No other scenario (except de novo synthesis by the trees) is even a little bit reasonable.

  9. Tristan says:

    That proposed biosynthetic pathway is pretty wild, in particular the “reduction” step in fig. 2 B is something you very rarely see in biology (the single case I can think of is the reduction of the prenyl chain in chlorophyll biosynthesis)

  10. Erebus says:

    Did they say which isomer they’re finding? Tramadol has several… but plants tend to stick to one, as opposed to racemic mixtures.

  11. dave w says:

    #4 – easier way to do that I think – introduce labeled tramadol into the supply chain and see if the label isotopes appear in the “tree tramadol”…

  12. Danny Sichel says:

    #11 – I don’t think the farmers would be too pleased to know that they were being sold drugs that had been labeled with DEADLY RADIATION !!!1!!!111!!eleven!

    1. David Edwards says:

      Stable isotope labelling?

      Deuterium, carbon-13 and oxygen-18 are all available. There’s also nitrogen-15, three stable sulphur isotopes if you need to label a thiol group etc., and if your molecule is chlorinated, you can run up a batch using pure chlorine-37 as your halogen source. I’m not saying it would be easy, and would also probably be expensive, probably too expensive to throw around the Cameroon countryside to answer this question unless you can persuade some Wall Street types to divert some of the money they’d otherwise spend on mansions and yachts, but it’s entirely possible.

  13. Hammilton says:

    Danny Sichel- Well, it’s not like Cameroonian farmers will be suing you.. kidding of course.

    Surely there are samples of this tree growing elsewhere. There are sites online that sell an extract (and were doing so before the first paper)

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