OHSU researcher publishes first measurements of "free-base" nicotine in cigarette smoke

Thought to be the most addictive form of nicotine in tobacco smoke, free-base nicotine is found at a wide range of levels in popular brands

When it comes to nicotine content, all cigarettes are not created equal, according to a new study by researchers at Oregon Health & Science University. In fact, the study finds that some commercial cigarette brands contain 10 to 20 times higher percentages of nicotine in the so-called “free-base” form — the form thought to be most addictive — than believed up to now. The study, published today in the online edition of the American Chemical Society´s journal Chemical Research in Toxicology, documents the first reliable measurements of free-base nicotine in tobacco smoke.

“We believe that this study is a major step forward in understanding how addictive nicotine is delivered by tobacco smoke,” said James F. Pankow, Ph.D., professor of environmental and biomolecular systems at OHSU´s OGI School of Science & Engineering in Hillsboro, Ore., and a member of the OHSU Cancer Institute. “We found big differences in the percentages of free-base nicotine among 11 commercial cigarette brands.”

Nicotine enters a smoker´s body mostly carried on the billions of particles in cigarette smoke, Pankow said. In common with street drugs like cocaine, he said, nicotine´s molecular structure can appear in both free-base (“unprotonated”) and non-free-base (“monoprotonated”) forms. The difference is that the free-base form is missing a hydrogen ion, and this allows it to vaporize easily into a gas during smoking. “During smoking, only the free-base form can volatize from a particle into the air in the respiratory tract. Gaseous nicotine is known to deposit super-quickly in the lungs. From there, it´s transported rapidly to the brain.

“Since scientists have shown that a drug becomes more addictive when it is delivered to the brain more rapidly,” Pankow continued, “free-base nicotine levels in cigarette smoke thus are at the heart of the controversy regarding the tobacco industry´s use of additives like ammonia and urea, as well as blending choices in cigarette design.” A 1997 Pankow study resulted in the first public-domain report linking ammonia additives with increased free-base nicotine levels.

In the new study, Pankow analyzed the smoke of popular cigarette brands under controlled conditions to measure what percentage of the nicotine is in the more addictive free-base form. It employed a laboratory smoking device and a gas chromatograph-mass spectrometer (GC-MS) to collect and analyze smoke from 11 brands of cigarettes purchased at various U.S. retail outlets. These cigarettes were tested against a “reference” cigarette — a standardized cigarette used only by scientists in tobacco and smoking research. The researchers made brand-to-brand comparisons, measuring the first three puffs of smoke from each brand separately from the remaining smoke. The first few puffs, Pankow said, “are in some cases much higher in this free-base nicotine fraction.”

Measurements ranged from about 1 percent free-base nicotine in the first few puffs of the reference cigarette to 36 percent for a specialty U.S. brand. One type of Marlboro, the leading U.S. brand of king-sized filter cigarettes, contained about 10 percent free-base nicotine, Pankow said.

The study found a wide range of free-base nicotine levels among other brands such as Camel, Winston, Doral, GPC, Kamel Red, Virginia Slims, American Spirit and the French brand Gauloises. (A copy of the complete study is available upon request; see the last page for details).

Neal Benowitz, M.D., a nicotine addiction expert at the University of California at San Francisco School of Medicine, provided a scientific perspective of this study´s impact:

“The rate of absorption of nicotine from a tobacco product into the blood stream influences the addictiveness of the product, and the rate of absorption of nicotine from cigarette smoke is dependent on how much of the nicotine is in the free-base form. Free-base nicotine levels are determined by the pH (acid-base balance) of the smoke, which is difficult to measure accurately and which can be influenced by various additives. Pankow and colleagues have analyzed free-base nicotine and pH in a number of popular cigarette brands, using a novel method that is much more accurate than methods used previously. They found more than 10-fold variation in levels of free-base nicotine among American cigarette brands. This is the first research to make such observations and will certainly help to guide future research into differences in the addictiveness of different brands of cigarettes.”

Internal documents made public through the 1999 tobacco settlement show that some industry scientists have long been aware of the role of free-base nicotine in cigarette smoke. For example, one report in the Legacy Tobacco Documents Library states:

“In essence, a cigarette is a system for delivery of nicotine to the smoker in attractive, useful form. At `normal´ smoke pH, at or below about 6.0, essentially all of the smoke nicotine is … relatively slowly absorbed by the smoker. As the smoke pH increases above about 6.0, an increasing proportion of the total smoke nicotine occurs in “free” form, which is volatile, rapidly absorbed by the smoker, and believed to be instantly perceived as nicotine “kick,” R. J. Reynolds Tobacco Company, 1974.

Pankow notes that most addiction researchers believe that chemicals like nicotine, cocaine and methamphetamine become increasingly addictive the more rapidly they are delivered to the brain. Addiction expert Jack Henningfield, Ph.D., a professor at the Johns Hopkins University School of Medicine and former adviser to past FDA Commissioner David Kessler, M.D., J.D., said Pankow has shown that ” cigarettes deliver much higher levels of free-base nicotine than previously thought, thus helping to explain their enormous addictive potential. In fact, the study shows that the modern cigarette does to nicotine what crack does to cocaine. It appears likely that ingredients used in modern cigarette manufacture such as ammonia and urea account for this addiction-enhancing effect.”

According to Greg Connolly, D.M.D., M.P.M., director of the Massachusetts Tobacco Control Program, the study “will allow a consideration of the regulation of the addictive properties of cigarettes in a way that has never before been possible.”

Coincidentally, the study comes on the heels of a recent controversy in Europe over the disclosure of tobacco ingredients. Last week, Dutch Health Minister Han Hoogervorst ordered tobacco manufacturers to make public all ingredients used in cigarettes, cigars and loose tobacco sold in the Netherlands, and to reveal which ingredients are addictive. The new rule — which also applies to foreign-based companies — was issued over the protests of tobacco companies concerned about the disclosure of proprietary product information. According to an April 25 Reuters report, BAT Netherlands, a subsidiary of the tobacco giant British American Tobacco, objected to the disclosure of additives used in cigarettes sold in the Dutch market. A spokesman for the company stated:

“… to our understanding this requirement goes beyond what was required by the EU directive and it is most detrimental to our position vis-a-vis our competitors, and certain information cannot be declared . . . .”

Dutch officials stated that the government would not reveal specific tobacco formulations, preventing competitors from copying a specific brand of cigarette. In the United States, there are no formal tobacco industry or FDA guidelines covering the appropriate levels of free-base nicotine in cigarettes, Pankow said. “But the `conventional wisdom´ put forth by the industry in the past suggested small percentages of free-base nicotine,” he said.

“Cigarette smoking is the single most preventable cause of morbidity and mortality in the United States,” said Grover C. Bagby, Jr., M.D., director of the OHSU Cancer Institute. “Understanding the chemical elements that form the basis of addiction is an important step forward in developing ways of conquering this problem in our society today.”