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The Case For Non-Biogenic Tramadol

The battle over whether tramadol is a natural product or not has been a heated one. Over the last couple of years, it was reported to be produced by a west African shrub, then this was reported to be an artifact of feeding the drug to cattle, and then this hypothesis was challenged by work on an actual biosynthetic pathway. The latest cannonball to be fired might end the debate, although I’m not sure I’d bet on that just yet. It’s from the Dortmund group that reported the tramadol contamination problem, and they’ve returned to the area of North Cameroon (with a colleage from the University of Mourou there) to analyze the material using accelerator mass spectrometry (AMS).

The idea is to measure the amount of carbon-14 in the tramadol itself. Natural products get their carbon, fundamentally, from carbon dioxide in the environment, fixed by photosynthetic organisms into material for the food chain. As such, there should always be some radioactive carbon in there, since it’s being continually produced in the upper atmosphere from nitrogen atoms interacting with cosmic rays. This is the whole idea behind carbon dating – a continual source of 14C. Synthetic organic compounds, though, tend to be made from precursors that are ultimately derived from petroleum/natural gas feedstocks. These have been sitting underground for an extended period, not exchanging very much carbon with the surrounding environment, and are thus depleted in carbon-14. You need some pretty hard-core analysis to detect this sort of thing (thus AMS), but the differences are large once you can see them. (As an aside, the various people who are convinced that a “natural” compound is just somehow different than the identical molecule prepared by synthetic routes may not realize that yes, in some cases the all-natural one is slightly more radioactive).

The authors grew the plant in question (Sarcocephalus latifolius) from seed and confirmed that (1) it had no tramadol in its leaves or roots as grown, (2) that when fed with labeled phenylalanine (the starting material for the previously proposed biosynthetic pathway), that this was taken up and converted to various intermediates, but not to any detectable tramadol, and (3) that when plants were grown in tramadol-laced soil, that they did indeed take up the compound into various tissues.

There are many field observations in the paper as well. Tramadol, as purchased from a street vendor in Cameroon, has (as expected) very low 14C content, consistent with it being a compound derived (ultimately) from petroleum sources. Various locations around northern Cameroon were found to have tramadol in the soil, rivers, and drinking water (!), and all of these samples also showed the same low levels of 14C. Sampling the plants in these regions gave highly variable results. Many of them had no detectable tramadol at all, but the amounts found in them (and in soil samples) seemed to correlate well with collection during the rainy season, which also suggests anthropogenic contamination. In short, the whole area is laced with synthetic tramadol in various concentrations, some of them rather alarmingly high – the drug is clearly a persistent contaminant in the environment, and this really does seem to be the source of it in plant samples.

So unless someone can demonstrate tramadol with higher radiocarbon content, or (especially) show that it is produced in plants grown under controlled conditions, this case would seem to be closed. We’ll see if it really is, though. . .

15 comments on “The Case For Non-Biogenic Tramadol”

  1. Food Babe says:

    “Synthetic organic compounds, though, tend to be made from precursors that are ultimately derived from petroleum/natural gas feedstocks. These have been sitting underground for an extended period, not exchanging very much carbon with the surrounding environment, and are thus depleted in carbon-14.”

    Hah, now I have caught you out red-handed!

    You have just contradicted all your earlier arguments by explaining that synthetic organic compounds are NOT the same as natural compounds, because synthetic compounds are … err … less radioactive!

    OK, time to eat only synthetic vegetables from now on.

  2. haarpo says:

    What when the synthesis (even from fossile carbon) is slightly more selective towards c14? Or is carbon too heavy to make a difference already?

  3. John Wayne says:

    My roommate in graduate school used to wonder if an enzyme could select for an isotope; fascinating idea.

  4. mike says:

    PLEASE PLEASE PLEASE tell me that the comment above is from someone impersonating Food Babe with the aim of making her look like an under-educated simpleton!

  5. dave w says:

    Seems like the exception would be if a drug were synthesized from a natural-product source… for example AIUI some of the steroid hormones (such as estradiol) can be manufactured from sterols derived from soy plants.

  6. Mark Thorson says:

    An exception in the other direction would be natural products from plants raised on carbon dioxide in exhaust gases from fossil fuel power plants. This has been done experimentally for carbon capture.

  7. David B says:

    Good piece!
    I do have one concern from this; you mention that the evidence seems to be pointing to persistent environmental contamination by Tramadol. If so, where is it coming from? And, what other regions of the world are similarly contaminated? Furthermore, what is known in general about envirnmental contamination by medicines? Is this a common situation? I don`t know, hence my questions.
    Cheers.

  8. Mark Thorson says:

    Follow the first link at the start of the article, and it will tell you where the Tramadol comes from. That will link to other earlier articles which go into more detail.

  9. aairfccha says:

    About environmental contamination by medicines: Diclofenac and ethinyl estradiol are the (to me) best known examples. One is released in considerable amounts and is toxic for vultures, the other is a hormone.

  10. Food Babe says:

    @mike:

    No, I really am the Food Babe!

    (but it’s also true that I’m just a really thick under-educated simpleton. 😉

  11. Kevin says:

    @Dave w: Yes, it’s true that one could produce a synthetic compound with “natural”-looking (high) C-14 content. (Though every time you modified your natural starting compound, you would have to take care to use reagents containing biogenic carbon with the same high C-14 content, lest you dilute your “natural” C-14 signature. How much C-14 is there in off-the-shelf methyllithium, say?)

    This test is only conclusive in one direction–it can demonstrate that an observed compound is not biogenic, since that’s pretty much the only way to get depleted C-14. It can’t (quite) prove something is biogenic, since in principle it is possible to produce synthetic compounds with high C-14 levels.

  12. Curt F. says:

    When the previous salvo was fired, I was intrigued but not quite convinced that tramadol might be a natural product. This work, though, is dispositive evidence that it is not. I was wrong that the best technique to use to establish origins was position-specific hydrogen isotope studies at natural abundance. Accelerator mass spectrometry is much better suited to the task; the authors use it successfully and convincingly.

    Lost in the brouhaha is the fact that tramadol contamination of the natural environment is apparently endemic in some Cameroon well water:


    Large amounts of tramadol could be detected in thepublic-well water samples collected at BP7 during our firstcampaign (1610 ng/L) but also during our second campaign(325 ng/L), along with the highly active metaboliteO-DSMT, as well as N-desmethyltramadol (N-DSMT), and4-hydroxycyclohexyltramadol (4-HCHT; see Table S3).

    That means it would take drinking 500+ liters of water to get a “therapeutic” dose, but I don’t think anyone has any idea what the effects might be when an entire population is chronically dosed with sub-therapeutic levels of an anti-psychotic, anti-depressive drug, anagesic drug.

  13. tangent says:

    Yeah, this result is almost as wild as the biogenic claim, and certainly more relevant to Cameroonians. Just how much tramadol is being spread over the countryside?

    Let’s see, if we distribute 1 kg tramadol over 1 km^2, that’s 1 mg per m^2. If it’s mixed into groundwater to a depth of 1 m of water (is there a hydrologist in the house?), that’s 1 μg/liter, 1000 ng/L, order-of-magnitude what they detect.

    So I guess that’s not actually insane, if you’re dishing it out to cattle. If you dose a 500 kg cow at 1 mg/kg, we’re talking just 2000 cow-doses of drug deposited across our km^2, and then adjust for soil life versus dosing schedule.

    Tangent from that: I knew I was scared about antibiotics in livestock, but I didn’t realize I should be scared about livestock antibiotics throughout the topsoil.

    Crossing my fingers the tramadol isn’t hurting people at the level it’s present in hotspots, but I hope somebody’s got funding to study it. And look for what the hell else might be in that Brompton cocktail drinking water.

  14. Soon-to-be-former BMS person MOLS says:

    A note on carbon dating: thousands of years from now, dating artifacts from the 20th century will be rather complicated due to atom bomb tests during the Cold War (peaked circa 1963).

    For certain purposes, such as scientific instruments that are particularly sensitive to radiation, steel from old ships is preferred to modern steel:
    https://en.wikipedia.org/wiki/Low-background_steel

  15. Derek Hook says:

    Isn’t Tramadol marked as a mixture of R & S stereo-isomers?

    If so have the material isolated from the plant been tested for R/S ratio ?

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