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Analytical Chemistry

Weirdly, Tramadol Is Not a Natural Product After All

Last year I mentioned a paper that described the well-known drug tramadol as a natural product, isolated from a species of tree in Cameroon. Rather high concentrations were found in the root bark, and the evidence looked solid that the compound was indeed being made biochemically.
Well, thanks to chem-blogger Quintus (and a mention on Twitter by See Arr Oh), I’ve learned that this story has taken a very surprising turn. This new paper in Ang. Chem. investigates the situation more closely. And you can indeed extract tramadol from the stated species – there’s no doubt about it. You can extract three of its major metabolites, too – its three major mammalian metabolites. That’s because, as it turns out, tramadol is given extensively to cattle (!) in the region, so much of it that the parent drug and its metabolites have soaked into the soil enough for the African peach/pincushion tree to have taken it up into its roots. I didn’t see that one coming.
The farmers apparently take the drug themselves, at pretty high dosages, saying that it allows them to work without getting tiree. Who decided it would be a good thing to feed to the cows, no one knows, but the farmers feel that it benefits them, too. So in that specific region in the north of Cameroon, tramadol contamination in the farming areas has built up to the point that you can extract the stuff from tree roots. Good grief. In southern Cameroon, the concentrations are orders of magnitude lower, and neither the farmers nor the cattle have adopted the tramadol-soaked lifestyle. Natural products chemistry is getting trickier all the time.

18 comments on “Weirdly, Tramadol Is Not a Natural Product After All”

  1. The Aqueous Layer says:

    Holy Sh….
    Nevermind.

  2. SteveDoc22 says:

    Great detective work by the authors! Context is always important. And so that’s what they mean by “contented cows”.

  3. Wile E. Coyote, Genius says:

    My guess is that they are giving to oxen – beasts of burden – so that they can pull a plough longer?

  4. luysii says:

    I suppose you all know that tramadol binds to the mu opiate receptor and inhibits the reuptake of norepinephrine and serotonin. No wonder the farmers are happy. However, nearly 20 years ago there were 83 reports of convulsions due to it (but most of these folks were on other drugs — tricyclic antidepressants, monamine oxidase inhibitors.

  5. CMCguy says:

    I wonder is the synthetic version given to the animals a chiral mixture? And if so are the unmodified product isolated the same isomers as the metabolite species? Might be a unique way to separate isomers (ingestion-extrusion pathway?) but imagine probably not commercially viable unless the byproduct can be sold as fertilizer.

  6. Fozz E. Bear. says:

    wait, what type of receptor does tramadol bind to?
    the MOO opiate receptor!
    wocka wocka.

  7. Curt F. says:

    A couple of notes:
    1. Is this the first time that ethnographic research has found its way into the pages of Angewandte Chimie? Very cool that the authors took the time to interview farmers.
    2. Hindsight is 20/20 and all that, but looking back the presentation and discussion of the isotope-ratio data in the original paper is a bit suspect. In particular, from the original paper: Negligible differences can be seen between the natural and commercial samples on the basis of the 13C values, which indicates that the majority of the carbon atoms in the commercial samples probably derive from a C3 plant biological origin. Well, that seems to be question-begging. It suggests only that the carbon in “natural” and synthetic tramadol comes from the same place, not that that place is necessarily C3 plant metabolism. The right comparison would have been to 13C isotope ratios to other bona fide natural compounds (ideally also alkaloids) isolated from N. latifolia. And it seems like given FDA regulations and cGMP sourcing requirements, whether commercial tramadol is actually synthesized from C3 plant carbon would be something that could easily be verified. Does anyone know what starting materials are used for commercial synthesis of tramadol?
    3. The original authors added that position-specific 2H/1H isotope ratios would be dispositive and suggested they planned to do that analysis eventually. I agree — position-specific 2H/1H ratios would probably be the single best technique to differentiate biosynthesis to nearly all commonly used chemical syntheses. It’s a shame that so few laboratories in the world are set up to do these admittedly very difficult measurements. (In general it requires large sample sizes and very long, careful deuterium NMR [“SNIF-NMR”] experiments, although in some cases chemical derivatization and GC-IRMS can be used; e.g., demethylation with HI and GC-IRMS on released methyl iodide for determination of 2H/1H of aryl methyl groups).

  8. Derek Lowe says:

    #7 Curt F –
    I’ve never had to mess with single-position isotope ratios, that’s for sure. It does indeed sound like a major pain.
    As for the synthesis, I don’t know what route people are using in India (or wherever). But the original route (US3652589) is addition of the Grignard or lithio derivative from 3-bromoanisole to a cyclohexanone Mannich base, and then resolution. Most of the patent activity in more recent times seems to be improvements of the resolution, so this may well still be the chemistry.

  9. Curt F. says:

    @9. Derek Lowe – Thanks for the reply! I’m not enough of an organic chemist to know whence 3-bromoanisole would ultimately derive, but it is probably benzene. And the cyclohexanone is probably also from benzene. I found one paper that reported surveying δ13C values for a variety of commercial benzenes. (http://www.sciencedirect.com/science/article/pii/S0146638099000595) They found values of between -24 per mil and -30 per mil. That significantly overlaps the range for tramadol (-29 to -33) found in the paper. It’s hard to know how 13C is fractionated at the various steps of benzene (or other SM) conversion to phenol, 3-bromoanisole, etc., so the overlap says to me only that the δ13C evidence isn’t very informative one way or the other. The more I think about it the less value it provides to the original paper.
    The 15N evidence is similarly unimpressive, but in hindsight it also tells us something interesting. It suggests the two “natural” samples studied in the original paper, even though they were collected a year apart from different plants in different locations, were probably derived from the same batch of tramadol (or at least from tramadol made from the same source of methylamine.)
    The reason natural-abundance 2H/1H is so informative is that fractionations are huge, providing a larger dynamic range, and organic chemistry tends to make C-H bonds in much, much different ways than biochemistry. (Cyclohexanone comes from hydrogenation of benzene followed by oxidations of benzene vs. either shikimate or terpene pathways in biochemistry). Position specific 2H/1H measurements at natural abundance are very hard, but thinking more, total-molecule 2H/1H, far more accessible via standard GC-IRMS methods, and comparison to 2H/1H levels of the xylem water of the sampled trees, would also likely have been determinative.

  10. oldnuke says:

    I wonder if some of the cattle are suffering from seizures out in the pasture?
    The thought of Elsie The Cow seizuring in the pasture is just so wrong!

  11. CraigMacTG says:

    I feel like there’s a Dune reference to be made here.

  12. Gidog says:

    Has is never occurred to any of you that the poor cows might have had chronic back pain and quite simply needed relief. Why do us poor farmers always get ridiculed for being uneducated Hicks. I learnt not long ago why my sheep weren’t growing well for example and now I don’t plant then so deep. We’re not all stupid.

  13. Tleilaxu Ghola says:

    It is interesting where the internet can take you sometimes. I have diabetic neuropathy in both of my legs and feet. I have had just about every drug prescribed for the pain that I have. For years now I have been taking Lyrica (for the prickling burning pain in feet) and Tramadol (for the deep, headache-like pain in my legs) I have asked more than one M.D. why it is that Tramadol, more than anything else I have been given (from Oxy, Morphine, Dilaudid, every over the counter med, etc) works SO well for that particular leg pain I have. Hands down better than more exotic/stronger pain medicines.
    I guess I will ask here; Why does Tramadol work so much better on neuropathy leg pain than anything else, so far no Doctor I have been to over the years has been able to give me an answer. Any insight would be welcomed.
    At the very least I have a new avenue of investigation for this question whose answer has, thus far, eluded me over these years.

  14. Tleilaxu Ghola says:

    It is interesting where the internet can take you sometimes. I have diabetic neuropathy in both of my legs and feet. I have had just about every drug prescribed for the pain that I have. For years now I have been taking Lyrica (for the prickling burning pain in feet) and Tramadol (for the deep, headache-like pain in my legs) I have asked more than one M.D. why it is that Tramadol, more than anything else I have been given (from Oxy, Morphine, Dilaudid, every over the counter med, etc) works SO well for that particular leg pain I have. Hands down better than more exotic/stronger pain medicines.
    I guess I will ask here; Why does Tramadol work so much better on neuropathy leg pain than anything else, so far no Doctor I have been to over the years has been able to give me an answer. Any insight would be welcomed.
    At the very least I have a new avenue of investigation for this question whose answer has, thus far, eluded me over these years.

  15. jack says:

    Tleilaxu Ghola,
    You should consider trying Kratom instead of pharmaceuticals. It’s safer, and more effective. Research “Mitragyna Speciosa”, and become a member of the Kratom Connosieurs forum for more info. I’ve medicated my father who had over 5 back surgeries and a hip replacement successfully for long term pain management for over 2 years now. It works better than any traditional pain management therapy that I know of so far.

  16. RBW says:

    ‘Natural products chemistry is getting trickier all the time.’
    No, Derek, it isn’t! Natural product chemists are getting shoddier…
    This is just like the Tetrahedron report of the Boehringer drug nevirapine found naturally that was discussed here and eventually retracted. Or other papers that have reported synthetic benzodiazepines etc. as naturally occurring.
    Any chemist who isolates a compound with a scaffold unprecedented in nature that ALSO happens to be a human drug made synthetically needs to proceed with extreme caution. Believe that you are guilty of finding an artifact unless you can prove innocence. It may happen but the odds of striking the lottery are just as good.
    In the old days when I was at Harvard and a decent chemist, we isolated bucketloads and did all those degradative studies that linked compounds biosynthetically in a credible way.

  17. RBW says:

    ‘Natural products chemistry is getting trickier all the time.’
    No, Derek, it isn’t! Natural product chemists are getting shoddier…
    This is just like the Tetrahedron report of the Boehringer drug nevirapine found naturally that was discussed here and eventually retracted. Or other papers that have reported synthetic benzodiazepines etc. as naturally occurring.
    Any chemist who isolates a compound with a scaffold unprecedented in nature that ALSO happens to be a human drug made synthetically needs to proceed with extreme caution. Believe that you are guilty of finding an artifact unless you can prove innocence. It may happen but the odds of striking the lottery are just as good.
    In the old days when I was at Harvard and a decent chemist, we isolated bucketloads and did all those degradative studies that linked compounds biosynthetically in a credible way.

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