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Memory Therapy Promising to Curb Smoking

Researchers are gaining ground in developing ways to weaken maladaptive reward memories to curb smoking behavior.

Two articles published online February 1 in JAMA Psychiatry describe separate strategies to modify maladaptive reward memories in smokers during reconsolidation, the process by which long-term memories may be updated.

Maladaptive reward memories are formed when functioning of the brain’s reward-learning system is “hijacked” by addictive drugs, including tobacco. But research suggests that memories may be permanently changed if they are first retrieved and then changed through incorporation of new information.

“The theoretical argument is that when you initially present stimuli, you’re activating the memories, and those memories are now in a vulnerable state; they’re actually open to being modified before they’re restabilized in long-term storage,” explained Michael E. Saladin, PhD, professor, Department of Health Sciences and Research, College of Health Professions, Medical University of South Carolina, in Charleston.

“If you do a manipulation at that point, whether it’s pharmacological or behavioral, the theory is that you can impact those memories and change the behaviors associated with those memories,” he told Medscape Medical News.

Dr Saladin is an author of one of the studies, with first author Lisa J. Germeroth, PhD, also at the Medical University of South Carolina. It included participants who had smoked 10 or more cigarettes a day for at least 3 years and were willing to attempt a 3-day cessation without aids, smokeless tobacco, or electronic cigarettes.

They were randomly assigned to one of two groups. The retrieval-extinction (R-E) group watched a 5-minute video depicting people smoking cigarettes (a conditioned stimulus [CS]) and then received extinction training. The second group, the nonsmoking-related retrieval followed by extinction (NR-E) group, watched a neutral video and then received extinction training.

The two groups watched the videos on two consecutive days. After each viewing, the participants received extinction training, which was identical for the two groups.

“The idea in having the control is to show that the retrieval experience confers a benefit that you don’t see with extinction training alone,” said Dr Saladin.

Extinction Training

The goal of extinction training, he explained, is to change the information content of the memory. “The former content of that memory was that smoking cues are followed by nicotine reinforcement, nicotine reward, nicotine psychopharmacology. When you do extinction training, you’re substituting a different kind of content, and the content is that smoking cues are no longer associated with nicotine reward.”

Craving was assessed at the two training sessions and at 24 hours, 2 weeks, and 1 month using the self-report Craving Questionnaire. Smoking abstinence was checked using self-reports and breath carbon monoxide (CO) levels.

Of the 88 participants, 98.9% attended at least one training session, 86.4% attended at least one test session, and 81.8% attended all test sessions.

The investigators found that compared to NR-E training, the R-E training significantly reduced the mean craving rating (P < .05). Both groups had a high level of craving on the first day of training, but an effect was already starting to emerge on the second day. By the 1-month test, “there is a substantial change,” commented Dr Saladin.

The retrieval-extinction intervention also had a significant effect on the number of cigarettes smoked per day. “On average, there was approximately a 26% greater reduction in smoking between groups,” said Dr Saladin.

The self-reported smoking findings were corroborated by assessment of CO levels at 1 month.

There was no between-group difference in urine cotinine levels, which the authors said was unexpected given the findings regarding craving, smoking levels, and CO level. However, they said, urine cotinine levels likely are not sufficiently sensitive to reveal group differences in the number of cigarettes smoked per day.

There were no effects on heart rate or blood pressure associated with the intervention.

Dr Saladin would like to follow these participants for 6 months. “It looks like the two groups are starting to separate even more” at the end of this study, “so I’m thinking we might be surprised by what we will see later on.”

This type of intervention does not require a large time commitment and would be relatively easy to incorporate into practice – probably in a clinic setting. However, it should not be a stand-alone treatment, said Dr Saladin.

“Smoking behavior is very complex, meaning it’s determined by a lot of things, and you can almost rest assured that treating a behavioral disorder is going to involve different facets.”

This R-E training approach “helps people dampen their smoking” in conjunction with, for example, smoking cessation medications or cognitive-behavioral therapy, said Dr Saladin.

He and his colleagues believe that this type of approach could easily be adapted to treat other substance use disorders or anxiety disorders, such as posttraumatic stress disorder.

Propranolol Administration

The second study, led by Yan-Xue Xue, MD, PhD, National Institute on Drug Dependence, Peking University, China, used a different approach – brief smoking, an unconditioned stimulus (UCS) – to reactivate relevant reward memories, and an oral pharmacologic amnestic ― propranolol, a common, safe, and well-tolerated drug – to disrupt these reactivated memories.

Dr Xue and colleagues also first carried out experiments in rats. Propranolol in combination with memory reactivation reduced nicotine-seeking in the animals.

A human experiment included 96 healthy young men who had been smoking 10 or more cigarettes daily for at least 12 months. Participants were advised to continue their normal smoking habits and not to attempt to quit while participating in the study.

After providing baseline information, participants were shown a random series of images of different shapes and colors – some conditioned-stimulus (CS) positive, and others CS negative. Researchers carried out tests during which participants were exposed to newly learned and preexisting (or naturalistic) smoking cues while being asked to smoke or not smoke.

Participants were randomly allocated to one of three groups:

  • Placebo (40 mg) administered 1 hour before UCS (memory retrieval manipulation)

  • Propranolol 1 hour before UCS

  • UCS 6 hours before propranolol

Using information from a visual analogue scale (range, 0 – 5), the researchers measured subjective preference (“liking”) of newly learned and preexisting smoking cues and craving.

Because 27 participants did not complete the experiment, the analysis included 69 persons.

The study showed that preference of both newly learned and preexisting smoking cues decreased at 48 hours among those given propranolol 1 hour prior to smoking reward memory reactivation.

This was not found to be the case in those given placebo 1 hour before reactivation or in those who were administered propranolol after the 6-hour reconsolidation period. The authors note that 6 hours “is outside the temporal window” within which reconsolidation is thought to occur.

Craving in response to naturalistic cues was also reduced in the group that received propranolol 1 hour before the smoking reward memory reactivation.

The authors stress that the UCS-induced memory retrieval-reconsolidation inference procedure still needs to be tested in the smokers’ home environment.

The authors say they believe this approach holds promise as a method for decreasing nicotine craving and that its value should be tested for preventing smoking relapse.

Step Change

In an accompanying editorial, Sunjeev K. Kamboj, PhD, and Ravi K. Das, PhD, Clinical Psychopharmacology Unit, Research Department of Clinical, Educational and Health Psychology, University College London, United Kingdom, called the new findings important and exciting.

They said the studies highlight potential routes for minimally invasive plasticity-modulating treatments, which “could mark a step change in the treatment of tobacco use disorder and substance use disorders more generally.”

However, the results raise a number of questions. For example, the effects on subjective outcomes “were relatively circumscribed, restricted to very or relatively short-term reductions in subjective craving or liking in response to cigarette cues,” say the editorial writers.

“It remains to be determined whether the effects on smoking behavior observed by Germeroth et al extend over longer timeframes in smokers making a concerted effort to quit.”

The extent of memory restructuring achieved in these studies is also unclear, inasmuch as other clinically relevant, maladaptive reward memory–related outcomes were not examined, say Dr Kamboj and Dr Das.

They also note that it is not possible to attribute the findings of Dr Xue and colleagues solely to a weakening of memory during reconsolidation because propranolol was administered prior to UCS retrieval (instead of before retrieval, as in the rat experiments), “raising the possibility that it had additional effects at reactivation.”

The editorial writers also question the ease of implementation. UCS-reactivation techniques involving consumption of an addictive drug “are clearly problematic in patients who are already detoxed,” they write.

“Regardless, these promising translational successes provide reasons to be optimistic about the future of memory therapies for substance use disorders.”