Clinical Pharmacology of Nicotine Enantiomers

Summary/Abstract
Recently a number of electronic cigarettes (EC) brands have claimed to use liquids that are
“tobacco-free”, meaning they contain “synthetic” nicotine. Such products are not currently subject
to existing FDA tobacco control regulations and might be marketed to youth and others as cleaner
and less harmful than EC that contain nicotine derived from tobacco. E-cigarette manufacturers
may use synthetic nicotine as a way to avoid ongoing FDA regulatory processes for ECs.
Nicotine is a chiral compound with one asymmetric carbon atom and can exist as two mirror image
forms termed enantiomers or optical isomers, the levorotatory (S)-isomer and the dextrorotatory
(R)-isomer. While nicotine from tobacco is almost exclusive (S)-nicotine, most synthetic nicotine
is comprised of racemic (S)- and (R)- nicotine. Animal studies indicate that (S)- nicotine is more
potent than (R)- nicotine for most pharmacological effects, but the relative potency for different
effects varies considerably. Animal data also find differences in rates and pathways of metabolism
of the two nicotine enantiomers. Very little information exists on the human pharmacology of R
nicotine or racemic nicotine. Understanding the relative abuse potential, cardiovascular effects
and metabolic differences of the nicotine enantiomers and their racemic mixture is important for
appropriate FDA regulation of synthetic nicotine products.
We propose to conduct a human clinical pharmacology study using stable isotope methodology
to compare pharmacokinetics and pharmacodynamics of vaped (S)- and (R)- nicotine and
racemic nicotine. We will synthesize and prepare for human administration deuterium labeled (S)-
and (R)- nicotine.
In a crossover study, experienced EC users will on three separate days vape (S)-, (R)- or racemic
nicotine both in standardized sessions (15 puffs, one every 30 sec) and in a 90 min ad libitum use
session. Outcome measures will include pharmacokinetics, pulmonary retention, patterns of
nicotine metabolism, subjective and cardiovascular responses, and nicotine self-administration.
Of particular interest will be how in racemic nicotine mixtures (as found in many synthetic nicotine
products), the presence of (R)- nicotine affects the pharmacology and self-administration of (S)-
nicotine.

Grant Number: 5R01DA057282-02
NIH Institute/Center: NIH
Principal Investigator: NEAL BENOWITZ