Study in population living with HIV reflects findings in other groups and makes a strong case for cytisine approval in the U.S.

A large study published in The Lancet in 2016 demonstrated that medications for smoking cessation, such as varenicline (Chantix), helped in lowering smoking rates and bolstering efforts to quit.

More recently, researchers have focused on patients who both smoke and drink heavily, and therefore may derive especially robust benefits from changing those behaviors simultaneously.

Hilary Tindle, M.D., an internist and associate professor of medicine at Vanderbilt University Medical Center, founded ViTAL: The Vanderbilt Center for Tobacco, Addiction and Lifestyle, to build, formalize and fund smoking-cessation programs, as well as support research in Tennessee and beyond.

In a study published recently, Tindle and colleagues focused on the synergies of simultaneously treating smoking and alcohol. Tindle served as co-principal investigator, alongside colleagues in Russia and at Boston University, in examining the impact of varenicline, cytisine, and nicotine replacement therapy (e.g., patches, lozenges) in people living with HIV. The goal was to explore outcomes specific to this population, which is often excluded from clinical trials on addiction, and by extension, for a diverse general population of nicotine and heavy alcohol users.

“One very exciting aspect of the research was the ability to study cytisine, which is widely available in Russia, Poland, and other countries in Eastern Europe, but not yet here,” Tindle said. The study was published in August 2022 in JAMA Network Open.

Selection of HIV Study Group

The study population consisted of 400 participants – 263 men and 137 women – living in St. Petersburg, Russia. The average age was 39, and all were drinkers and smokers (about a pack a day) and averaged nine heavy drinking days per month, defined as days that include five or more alcoholic drinks for men and four for women.

“This population was recruited in part from a cohort that had been followed for over a decade and offered a reliable participation rate,” Tindle said. “Plus, as is common among people with HIV, rates of smoking and heavy drinking were high.”

Additionally, she points out that even well-controlled HIV is an inflammatory condition, so the inflammatory impacts of smoking and heavy drinking puts this population at elevated risk and therefore at a more urgent need for effective interventions.

“There is evidence of crosstalk between nicotine and alcohol at the nicotinic acetylcholine receptors in the brain that probably plays a major role in this effect we see.”

Equally Positive Outcomes

To assess the relative impact of the three types of nicotinic agonists on both smoking and alcohol behaviors, the researchers designated four study groups to receive one active medication and one placebo.

Group one received varenicline and a placebo mouth spray that did not contain nicotine; group two received placebo varenicline and an active mouth spray that did contain nicotine; group three received cytisine and a placebo mouth spray; and group four received placebo cystine and an active mouth spray.

Participants in all four groups reduced their alcohol intake and quit smoking at about the same rates, regardless of which medication they were assigned to.

By three months, in all groups, heavy drinking days dropped from nine to about two over the preceding 30 days and 84 participants (21 percent) had stopped drinking altogether. Similar abstinence rates were seen at six and 12 months.

Smoking rates also dropped, with 15 to 19 percent quitting altogether by six months, and rates remained low for up to 12 months. Those who quit smoking altogether also had much lower rates of alcohol intake – about half the number of heavy drinking days compared to those who continued smoking – an effect that continued over time.

“It appears that the solution has to do with fulfilling – or reducing or stopping – cravings that extend beyond just one substance,” Tindle said.

She says that overall, these quit and reduction rates are slightly less dramatic than those found in more diverse populations but are very close to findings in other populations with multiple health conditions.

“There has been an explosion of cytisine interest globally because it’s less expensive, doesn’t have as many side effects as varenicline, and is very well-tolerated.”

Crosstalk at Work

It is not clear why smoking cessation medication that targets nicotinic acetylcholine receptors would have any effect on alcohol intake. But Tindle says this outcome is in concurrence with the totality of evidence in human and animal literature. 

“There is evidence of crosstalk between nicotine and alcohol at the nicotinic acetylcholine receptors in the brain that probably plays a major role in this effect we see,” Tindle said.

She points to the particular significance of a nicotinic receptor that contains the alpha 4 subunit which, when stimulated in rats, causes them to forego alcohol.

In play as well are the psychological aspects of associating smoking and drinking with each other and with certain places, people and situations.

The Promise in Cytisine

While not yet FDA-approved for treatment of heavy drinking, , varenicline has been shown in placebo-controlled clinical trials to reduce alcohol craving and consumption. However, it can have side effects like nausea and vivid dreams, which tend to be sidestepped in cytisine. Additionally, some have had concerns that varenicline may cause worsening of depression. However, Tindle stresses that in studies this concern was determined to be unfounded..

Cytisine is now in phase 3 trials for smoking cessation in the United States, but this study is the first to test cytisine in humans for alcohol cravings.

“There has been an explosion of cytisine interest globally because it’s less expensive, doesn’t have as many side effects as varenicline, and is very well-tolerated, Tindle said.

One of the next steps will be testing nicotine agonists in a population of nonsmoking drinkers.

“This is challenging, since smoking and drinking most often go hand in hand, but it would be helpful to know if these medications help nonsmokers quit drinking,” Tindle said.

About the Expert

Hilary A. Tindle, M.D.

Hilary A. Tindle, M.D., M.P.H., is the William Anderson Spickard Jr., M.D., Chair in Medicine at Vanderbilt University Medical Center and founding director of the Vanderbilt Center for Tobacco, Addiction and Lifestyle (ViTAL). Her research centers on smoking cessation and impact of medications on reducing alcohol consumption.