The Cigarette and Vape Industry Won’t Support this Research, but CTSI Will

CTSI Supports a Broad Range of Smoking Research - From the Pharmacology of Nicotine, Informing Tobacco Policy and Rise in Electronic Cigarettes

Electronic & Tobacco cigarette
iStock: Neydtstock

Tobacco and nicotine research have deep roots at UC San Francisco (UCSF) dating decades back to when the tobacco industry denied the risks of smoking, its causal effects of lung cancer, heart disease and other health problems. A rising number of faculty are dedicated to tobacco related research – from documenting and understanding advertising strategies, manufacturing, marketing, scientific research and political activities of the tobacco industry, the pharmacology of nicotine, tobacco cigarettes and related products, to its repercussions on human health and the recommended policy measures to reduce the harms from smoking (the Center for Tobacco Control Research and Education, CTCRE, was established in 2001). The Clinical and Translational Science Institute (CTSI) has supported a wide range of this research and continues to as the smoking landscape evolves with the rise of electronic cigarettes and other novel tobacco products.

Early Human Studies on Nicotine and Informing Tobacco Policy

Neal Benowitz, MD, professor emeritus of medicine and former chief of the division of clinical pharmacology, has been conducting research at Zuckerberg San Francisco General Hospital (ZSFGH) since the early 70s and has authored more than 700 publications. He has utilized CTSI’s Clinical Research Services (CRS) when it was originally referred to as the General Clinical Research Center (GCRC). He has used the full range of inpatient, nursing and sample processing services throughout his career.

Benowitz works in clinical pharmacology and toxicology, as well as cardiology and heart disease. He first became interested in nicotine research because smoking is a major cause of heart disease. He ran some of the first studies on the human pharmacology of nicotine. Study participants were given nicotine by infusion or smoking cigarettes. His team studied the subjective, cardiovascular and hormonal effects of nicotine, the metabolism of nicotine, including racial, sex and genetic differences, nicotine addiction and later on, smoking cessation. Over time, his team evaluated various nicotine related products like patches, gums, waterpipes, and pipes.

“I used CTSI for virtually all of my research,” said Benowitz. “Blood samples, urine samples, blood pressure, heart rate monitoring around the clock - Clinical Research Services was absolutely essential in our research.”

Neal Benowitz (Left), Gideon St. Helen (right)
Neal Benowitz, MD, professor of medicine (left); Gideon St. Helen, PhD, assistant professor of medicine (right)

These studies spanning several decades have provided the fundamental science-base to support the regulation of tobacco products. Benowitz utilized CRS for his studies on the effects of reduced nicotine levels in cigarettes, which has shown to decrease dependence and addiction to smoking, and subsequently help some smokers quit. This research has translated to key rulings and policy by the Food and Drug Administration (FDA). In 1994, former FDA commissioner David Kessler (also, former dean of School of Medicine at UCSF), formally declared that nicotine was addictive based in part on Benowitz’s pivotal research. Later in 2009, the Family Smoking Prevention and Tobacco Control Act gave the FDA the authority to implement standards for tobacco products to protect public health. The FDA could regulate cigarette nicotine and ingredient levels.

More recently in 2018, the FDA ruled to reduce nicotine content in cigarettes – a first step in setting up a policy. Benowitz said, “The FDA is adopting this policy because of this research started at UCSF.”

As of now, there are no reduced nicotine content cigarettes on the U.S. market. “Tobacco companies have responded by saying consumers should be able choose between both high and low nicotine content cigarettes, but most smokers will always choose the higher, regular nicotine type for their fix. If all cigarettes had lower nicotine content, they would be less addictive,” said Benowitz.

His team estimates that the threshold of acceptable levels of nicotine for the smoker would be one half milligram content in the entire tobacco rod. Another factor to consider – if nicotine levels are too low, people could seek regular cigarettes through a black market.

“There are a few papers estimating the huge population benefit from regulating nicotine content, which most likely would be effective at reducing smoking more quickly and be less expensive than the full-blown anti-smoking campaigns that the public health has waged for many years,” said Benowitz. (See: Journal of Preventative MedicineNicotine Reduction Strategy: State of the science and challenges to tobacco control policy and FDA tobacco product regulation” and “The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts;” NEJM Special ReportPotential Public Health Effects of Reducing Nicotine Levels in Cigarettes in the United States”)

The Rise of Electronic Cigarettes

Participant smoking an e-cigarette, ZSFGH. Credit: St. Helen study team
Study participant smoking an e-cigarette, ZSFGH. 

Benowitz’s research in recent years along with a UCSF researcher he works closely with, Gideon St.Helen, PhD, assistant professor of medicine, has focused on electronic cigarettes (known as e-cigarettes). St. Helen originally started as a post-doctoral fellow with Benowitz. They use CTSI’s Clinical Research Services in-patient rooms in ward 5B at ZSFGH which have high efficiency filters and a camera recorder to look at puffing behavior, and number of puffs taken during smoking sessions.

The various studies have had people use their own e-cigarettes and/or regular tobacco cigarettes, looked at smoking desire over a 24-hour exposure, withdrawal symptoms, satisfaction, cardiovascular effects, profiled various types of e-cigarettes and how they differ in toxicant exposure. St. Helen has also researched e-liquid flavors and vaping behavior.

“Electronic cigarettes came on the scene in 2007, but have gained high popularity since 2011. The first study we did with CRS tried to establish how much nicotine is taken in and the pharmacokinetics of electronic cigarettes,” said St. Helen. People brought their own device and stayed in the research ward for one day. In the morning they took 15 puffs on the e-cigarette, with a period of abstinence to see how high the blood level of nicotine rises. After four hours of abstinence, the study team gave participants their own devices to use ad lib for 90 minutes to see the pattern of use over that time.

The nursing staff at 5B are very professional and competent. That’s one of the factors that makes our studies successful. There are very few facilities in the country where people can smoke in a hospital and be monitored as well as collect detailed pharmacokinetic data...We get high quality data.

Gideon St. Helen, MD

This study was the first to fully characterize how much nicotine was taken in by experienced e-cigarette users – above one milligram of nicotine, which is comparable to smoking a tobacco cigarette. It was also the first to show that most of the nicotine inhaled by the user stays in the user (i.e. systemic nicotine retention was higher ~94%). The study was published in Addiction in 2015. The team published “Nicotine Delivery and Vaping Behavior During ad Libitum E-cigarette Access” in Tobacco Regulatory Science the following year.

The second major study St. Helen ran with CRS examined the effects of different e-liquid flavors on nicotine intake and effects in experienced e-cigarette users. E-cigarette liquids, referred to as e-liquids, come in thousands of different flavors. “There is concern that these flavors appeal to youth, which can lead to initiation and use of e-cigarettes. There is also concern that flavors increase the addictiveness of e-cigarettes. On the other hand, flavors may be attractive to adult smokers who want to quit smoking with e-cigarettes. As such, the FDA needs data to understand how flavors can influence the overall public health consequences of e-cigarettes,” said St. Helen.

“We wanted to examine how flavors impact the rate at which nicotine is absorbed. Do the flavors change the patterns of usage of e-cigarettes?” St. Helen added. “The rate at which nicotine is absorbed into the body influences the addictiveness of tobacco products, as those that deliver nicotine more rapidly, such as cigarettes, are generally more addictive.”

The study cohort was made up of all adult, experienced e-cigarette users and mostly male, since they are the primary users of e-cigarettes in the Bay Area. For each flavor, they assessed the amount of nicotine taken in, how much nicotine was absorbed and how rapidly it was absorbed as well as the topography of use – puff duration and frequency of puffs. Participants used tobacco, strawberry and their own brand of flavor in this crossover study. 

“They stayed in the research ward for three days, which is really important to note, because without CTSI and this research facility, we could not do studies like that. It’s a ward with smoking rooms. We videotaped the sessions and looked at number of puffs taken, the interval between puffs,” said St. Helen.

Although nicotine content was the same for both tobacco and strawberry flavor e-cigarettes, the study team saw a slightly higher intake of nicotine with the strawberry flavor after 15 puffs on the e-cigarette. During the session where they could vape as they wanted, they used the strawberry flavor much more than the tobacco flavor, resulting in higher nicotine exposure with the strawberry flavor. They published the “Impact of e-liquid flavors on nicotine intake and pharmacology of e-cigarettes” in 2017, and the “Impact of e-liquid flavors on e-cigarette vaping behavior” in 2018 – both in the journal Drug and Alcohol Dependence.

St. Helen’s team recently finished a study comparing the cardiovascular effects and toxicant exposure of e-cigarettes with tobacco combustible cigarettes in dual users – studying the safety of these products. The manuscripts are under review.

Are e-cigarettes really an effective way to get people off cigarettes and if so, what could be the safest design for these e-cigarettes in terms of nicotine level and power of the devices? All of these factors could all inform FDA regulation.

Neal Benowitz, MD

“The nursing staff at 5B are very professional and competent. That’s one of the factors that makes our studies successful. There are very few facilities in the country where people can smoke in a hospital and be monitored as well asccollect detailed pharmacokinetic data. Some studies have a user vape an e-cigarette in the lab with one sample taken before and after,” St. Helen said.

“Further, we can enforce abstinence in the research ward since study participants can stay overnight for several days. Other studies have to send participants home where they may not be compliant with study protocol, which affects the validity of study findings. We get high quality data,” added St. Helen.

Benowitz’s team has several active studies as well as studies on the horizon where participants use e-cigarettes and tobacco cigarettes separately or jointly, as well as studies to examine the cardiovascular effects of vaping and smoking cannabis compared to smoking tobacco cigarettes – all of which use Clinical Research Services.

Learn more about Clinical Research Services

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The UCSF Clinical and Translational Science Institute (CTSI) is part of the Clinical and Translational Science Award (CTSA) program funded by the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) (Grant Number UL1 TR991872).