Synthetic Origin of Tramadol in the Environment

Abstract

The presence of tramadol in roots of Sarcocephalus latifolius trees in Northern Cameroon was recently attributed to point contamination with the synthetic compound. The synthetic origin of tramadol in the environment has now been unambiguously confirmed. Tramadol samples isolated from tramadol pills bought at a street market in downtown Maroua and highly contaminated soil at Houdouvou were analyzed by high‐precision 14C measurements by accelerator mass spectrometry (14C AMS): Tramadol from the pills did not contain any radiocarbon, thus indicating that it had been synthesized from 14C‐free petroleum‐derived precursors. Crucially, tramadol isolated from the soil was also radiocarbon‐free. As all biosynthetic plant compounds must contain radiocarbon levels close to that of the contemporary environment, these results thus confirm that tramadol isolated from the soil cannot be plant‐derived. Analyses of S. latifolius seeds, in vitro grown plants, plants from different origins, and stable‐isotope labeling experiments further confirmed that synthetic tramadol contaminates the environment.

Sulfadiazine Masquerading as a Natural Product from Scilla madeirensis (Scilloideae)

“…The lessons learned from the tramadol incident were considered by Hassan et al in 2017 after their isolation of the antidiabetes drug metformin from a specimen of Seidlitzia rosmarinus (Amaranthaceae) . The authors quickly determined that the metformin was an anthropogenic contaminant by analyzing its 14 C content, the same method used to prove the synthetic origin of tramadol from N. latifolia in 2016 . The examples of tramadol and metformin notwithstanding, to the best of our knowledge, no other cases involving the attribution of synthetic drug contaminants as natural products have been reported.…”

“…8 The authors quickly determined that the metformin was an anthropogenic contaminant by analyzing its 14 C content, the same method used to prove the synthetic origin of tramadol from N. latifolia in 2016. 5 The examples of tramadol and metformin notwithstanding, to the best of our knowledge, no other cases involving the attribution of synthetic drug contaminants as natural products have been reported. Herein, we report what appears to be another example of the isolation of an anthropogenic environmental contaminant (sulfadiazine) and its mistaken identity as a plant natural product from Scilla madeirensis (Asparagaceae, synonym Autonoëmadeirensis).…”

“…2 The authors were met with skepticism by their conclusion that tramadol was being produced naturally, 3 and, even after a convincing biosynthetic proposal, 4 it was ultimately determined that the tramadol was an anthropogenic contaminant arising from its off-label administration to livestock in the region. 5 The tramadol story has since served as a warning to natural products chemists to be wary of the potential isolation of synthetic contaminants from natural sources. This lesson is especially important in an age where environmental drug contamination, most notably from those used in the agricultural sector, 6 is very high.…”

“…(Rubiaceae) in 2013 garnered substantial attention from the scientific community in what would later be called “The Tramadol Wars” by medicinal chemist and columnist Derek Lowe . The authors were met with skepticism by their conclusion that tramadol was being produced naturally, and, even after a convincing biosynthetic proposal, it was ultimately determined that the tramadol was an anthropogenic contaminant arising from its off-label administration to livestock in the region . The tramadol story has since served as a warning to natural products chemists to be wary of the potential isolation of synthetic contaminants from natural sources.…”

“…Analysis of radiocarbon ( 14 C) levels provides an experimental platform to distinguish between carbon atoms recently incorporated into a molecule of interest via photosynthesis and those derived from petroleum-based precursors, where 14 C nuclides have long since decayed. , Unfortunately, the lack of access to the originally isolated sample or plant material precludes this analysis, and we cannot definitively rule out the possibility that sulfadiazine was biosynthesized by S. madeirensis or an associated microorganism.…”