Who Really did it First? Nature or a Pharmacist?

(September 22nd, 2014) Remember the tramadol story from last year? French researchers found that African trees synthesise the popular painkiller all by themselves. Now, German scientists claim that very different reasons are behind the trees’ alleged chem lab. The French fervently beg to differ.

Tramadol, an opioid analgesic, is frequently prescribed for the treatment of moderate to severe pain. Synthesised by German pharma company Grünenthal GmbH, it’s been officially sold since 1977. But to everybody’s surprise, scientists from France, Switzerland and Cameroon last year discovered that the African pin cushion tree (Nauclea latifolia), a medicinal tree, makes the compound, too. They measured very high concentrations of 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, or tramadol, in its roots. Now, researchers from the Institute of Environmental Research (INFU) in Dortmund (Germany) in collaboration with researchers from Cameroon have reportedly exposed a misconception regarding the presence of tramadol in these plants.

First off, Michael Spiteller and colleagues confirmed the original findings that tramadol is indeed found within the roots of Nauclea latifolia, although at much lower concentrations. They also found the drug to be present in many other plants growing in Cameroon. However, only plants growing in the northern region of the country contained tramadol, whilst the same species growing in the southern region did not contain detectable amounts of the drug. Spiteller told me “This was, of course a big surprise to us because in the beginning of our research we could not conclude why tramadol could only be detected in certain plants in the Far North.”

This intriguing finding led the authors to conduct interviews with farmers and local inhabitants at the collection sites. The interviews revealed that “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. (…) In the southern region, the use of tramadol is not known to farmers”. As a matter of fact, North Cameroonian farmers are consuming the pills in extremely high doses daily, “allowing them to work all day without feeling tired (...) when working throughout the day under the sun in extremely high temperatures”. Farmers also reported that tramadol is further fed to cattle when working them in their farms, so that the animals do not get tired quickly and to horses prior to horse racing. This could only mean one thing: waste from animals and humans was responsible for the discrepancies in findings between northern and southern regions. Indeed, water and soil in the northern region was found to contain tramadol, whilst further south, no contamination was uncovered. Spiteller told me the study highlighted that “researchers should be more cautious with the interpretation of so-called natural products with respect to their possible origin”.

And, there’s one more thought-provoking point – the health risk of the off-label use of tramadol in certain regions of Cameroon. Also indirectly, through consumption of contaminated drinking water (tramadol is highly water-soluble). These risks include “recurrent seizures, multiple organ dysfunction syndromes, and even death in humans”. Therefore, the authors say “Immediate measures should be taken to restrict the off-label use of tramadol in northern Cameroon.” Michael Spiteller told me, “We must be more aware about possible sources of contaminations by the off-label use of synthetic compounds like drugs, which exhibit high biological activity. Not only the contamination of the plant material but soil and drinking water may cause adverse effect especially to the children”. That’s why Spiteller’s group is now “looking for other drugs or highly bioactive compounds with off-label use, and will screen soil, water and plants for unknown anthropogenic contaminants.”

Spiteller and Co.’s findings seem to speak for themselves. But, at least, one person is not convinced – the lead author of the original study, Michel de Waard. He tells me the following: “We fully disagree with the conclusions (…) Reaching the type of concentration we identified in our sample supposes thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there (…) Soil contamination may also occur through tramadol leaching out of the trees, which is something not addressed at all by this group (…) We continue to think that tramadol is of natural origin for several reasons: we sampled our roots in a national park where livestock is fully prohibited; we have a veterinarian certificate stating that tramadol is not given to cattle. In the National Park of Bénoué, these trees are inhabited by gorillas and baboons that eat N. latifolia fruits (probably also containing tramadol). Their urine and faeces will also contaminate the soil, most likely explaining the presence of tramadol and its metabolites in the soil. These chemicals may then be picked up by other plants through anthropogenic contamination.” He went on to tell me, “We are in no way affected by these findings. Our work is now focusing on the natural pathway that is most likely used by the plant to synthesise natural tramadol.”

Michel De Waard also raised concerns about the “real motivations of this research group” given that “the financial interests around tramadol are huge and that the pharmaceutical industry would see the agricultural development of N. latifolia for the exploitation of natural tramadol with a very negative eye - something that is feasible with our reported concentrations”. De Waard also remarks, “We are sorry, however, that this study is presenting the African population as one that illegally produces and consumes tramadol and that negates the medical power of this plant in treating human diseases in Africa. It is a form of insult and contempt to their history and practices.”

So, who is right? What do you think?

Nicola Hunt

Photo: "Tramadol HCl" by LHcheM - Own work. Licensed under Creative Commons Attribution-Share Alike 3.0 via Wikimedia Commons

Last Changes: 11.01.2014