Not Just Your Average Bottle of Cough Syrup!
A Comparison of Dextromethorphan (DXM;D-3-methoxy-17-methylmorphinian), its Enantiomer, Levomethorphan (L-3-methoxy-17-methylmorphinian), and its Racemic Mixture, Racemethorphan

Hee Sun Chung, Sun Cheun Kim, Sang Ki Lee, Yong Hoon Park, Young Chan Yoo, and Yeo-Pyo Yun. “Simultaneous Analysis of D-3-methoxy-17-methylmorphinian and L-3-methoxy-17-methylmorphinian by High Pressure Liquid Chromatography Equipped with PDA.” Forensic Science International. 161.2-3 (Sept. 12, 2006) p185.

  • D-3-Methoxy- 17-methylmorphinan (Dextromethorphan, DXM), which is a structural analog of morphine and codeine, has been a popularly used non-narcotic antitussive (anti-cough) medication. It is a safe drug in therapeutic doses and does not produce analgesic effects, while its enantiomer, 1-3-methoxy-17methylmorphinan (Levomethorphan, LXM) is a potent narcotic analgesic.

  • DXM has been synthesized from a benzylisoquinoline (with a planar structure) by a process known as Grewe's cyclization to give the corresponding morphinan (with a three dimensional structure). The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl) isoquinoline (there is just one residual double bond at the fusion position of the two rings of the isoquinoline) is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan, or Racemethorphan.

  • This is a mixture of equal amounts of the (+)-isomer (Dextromethorphan) and the (-)-isomer (Levomethorphan) and this must be resolved into its two separate isomers. The racemic mixture (Racemethorphan) and the (-)-isomer (Levomethorphan) are both Schedule II drugs under the Controlled Substances Act, but the (+)-isomer (Dextromethorphan) has been exempted from scheduling.

  • Most chiral chemicals have different biological and pharmacological effects depending on their enantiomeric direction. DXM is an effective and safe antitussive and produces little or no central nervous system depression at the therapeutic dose, but it has phencyclidine (PCP, angel dust)-like effect and toxic psychosis in large doses. However, its enantiomer, LXM is a potential narcotic analgesic at the therapeutic dose. To obtain a hallucinogenic effect, young people usually take DXM in large amounts and many fatalities result from the overdose of this drug. Racemorphan (the racemic mixture of the two enantiomers) is much more potent than even the aforementioned levomethorphan because of the free phenolic hydroxyl. It is about three to four times as powerful as morphine, somewhat more powerful than even heroin (diacetylmorphine), and much longer acting than either.

  • Acute toxicity tests showed that the levo-rotatory isomers were more toxic than their corresponding racemates. These in turn were more toxic than their dextro-rotatory forms. The methyl ethers were more toxic than the parent compounds. Chronic toxicity studies have been carried out in rats and dogs on the racemates and in rats on levorphan and dextromethorphan.

  • This particular paper details the stereochemical analysis of DXM and LXM which is vital not only to identify starting materials for illegal drug manufacture but also to understand the trend of the chemical as an abused drug.

  • Levomethorphan (-)
external image 500px-Levomethorphan.svg.png
  • Dextromethorphan (+)
external image 500px-Dextromethorphan.svg.png

Additional Source:

Benson WM, Stefko PL, and Randall LO “Comparative pharmacology of levorphanol, racemorphan and dextrorphan and related methyl ethers.” (1953) J Pharmacol Exp Ther 109: 189-200.