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Clinical Pharmacology of Nicotine Enantiomers

Award Number: R01DA057282
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	000	2	6/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $700,343 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	000	2	5/28/2024	NON-COMPETING CONTINUATION	$700,343
														Subtotal = $700,343

Issue Date FY: 2023 ( Subtotal = $708,762 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	000	1	6/9/2023	NEW	$708,762
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	001	1	9/25/2023	NEW	$0
														Subtotal = $708,762

Grand Total All Awards = $1,409,105

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Clinical Pharmacology of Nicotine Enantiomers

Award Number: R01DA057282

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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