By Jeanene Swanson
There are, undoubtedly, many memories that addicts would love to forget. For most recovering addicts and alcoholics, encountering the so-called “people, places, and things” that remind them of using bring on the strongest cravings. Research has shown that repeated exposure to these cues—and then not getting to use—may temporarily ease cravings, but the association returns over time.
And, cravings equal relapse for the majority of addicts within the first year of sobriety. “Dealing with cravings is a major obstacle to recovery,” says Michael Saladin of the Medical University of South Carolina, “so it’s a natural target” for treating addiction. Saladin is one of a few clinical investigators who is looking at ways to interfere with cravings on the molecular level, such that these emotional memories can be erased.
Over the past several decades, science has slowly but surely upturned the entrenched idea of memory being relatively static—or, consolidated from “short-term” to “long-term” storage in the brain once and then left to deteriorate over the course of a lifetime. There is considerable evidence that memory can be interfered with during the initial consolidation period—both drugs that block protein synthesis in the brain and electroconvulsive shock can disrupt the formation of memories. It wasn’t until the late 1990s that researchers began really looking into the process of reconsolidation—what happens to memories when they are re-activated, or, recalled after they have been put into long-term storage.
In fact, recent research has found that memories are actually labile, in other words, open to being updated or changed during a short period of time after being recalled. A now-landmark study from 2000 out of Joseph LeDoux’s lab at NYU, and co-authored by Karim Nader, now at McGill University, found that they could erase fear memories in rats by injecting a chemical into their brains that stopped protein synthesis during a timeframe of about 6 hours after recall—they called this the “reconsolidation window,” and just like with new memories, reconsolidated memories require new proteins to be made. This reconsolidation window has most recently appeared on the radar of addiction treatment specialists as a way to interfere with—and possibly “erase”—craving memories.
There have been many studies looking at memory reconsolidation since 2000, but most have been done on rats. In all these studies it is important to understand the concept of fear extinction training. Harkening back to Pavlov’s classical conditioning studies, a neutral stimulus (say, a bell ringing) can be paired with a fearful stimulus (say, a shock to the rat’s foot) such that the rat learns to associate the neutral stimulus with the shock. After a while, the neutral stimulus alone will elicit a fear response. In fear extinction training, the subject is repeatedly exposed to the neutral stimulus—and continues to experience the fear without the actual shock—until the fear goes away. However, the extinction training can “wear off,” so to speak—this explains in part why addicts go back to using when they re-enter their old environments away from rehab, or simply, after a long enough period of time passes. Finding a way to interrupt memory reconsolidation in recovering addicts would go a long way toward preventing cravings and relapse.
Since drugs that block protein synthesis aren’t safe to use in humans, scientists have turned to drugs like propranolol (trade name Inderal), an FDA-approved beta-blocker that is already widely used to treat hypertension and stage fright. It works by lowering levels of the neurotransmitter norepinephrine, which, as it turns out, can also interfere with memory reconsolidation—norepinephrine is required for protein synthesis.
In the late 1990s, researchers at UC Irvine showed that propranolol could affect the emotional salience of a memory—while it can’t erase a memory, it can make it less emotionally relevant. The application of this work can be found in recent studies involving patients with PTSD—it might help victims of trauma dissociate their emotional memory from cues that remind them of what they went through, whether war-torn violence or domestic partner abuse. After decades of groundwork research, Harvard’s Roger Pitman found in a 2002 pilot study that exposing patients to propranolol immediately after a traumatic event might prevent them from developing PTSD.
Using these techniques to treat cravings in addiction is very new. In a study published in 2013, researchers tested rats to see if blocking memory reconsolidation with the drug rapamycin could reduce cravings. Led by Segev Barak, then at UCSF and now at Tel Aviv University, after putting alcohol-addicted rats through a 10-day abstinence period, they exposed them to the smell or taste of alcohol. Immediately after, they administered rapamycin, which apparently blocked the pathway that enables protein synthesis. Even without subsequent extinction training, these rats did not “relapse” a full 24 hours later. And, drinking remained “suppressed” for up to 14 days.
There are a handful of pre-clinical trials testing whether propranolol can work in addiction, namely for cocaine and nicotine. MUSC’s Michael Saladin led a study looking at treating cocaine addicts with propranolol during the reconsolidation window to reduce cravings and relapse. The results showed that it did, indeed, work: compared to addicts who received a placebo, those subjects who received an injection of propranolol after being presented with an initial cue “had greatly reduced craving response to [subsequent] cues” that they were exposed to the following day, as well as a variety of other subjective measures, he says, like reduced heart rate and blood pressure. He is currently conducting a follow-up study that will look at longer-term effects of propranolol exposure.
While much hype has been given to the idea of “erasing” memories using interventional techniques, all the researchers interviewed here said that this type of intervention—blocking reconsolidation of cue-based memories—is only going to change the emotional aspect to these memories. In essence, you’re not going to forget that you like the buzz from drinking or the high from doing drugs; the association for the drug with a cue—the craving—is just going to be diminished. The memory itself is not being changed, Saladin says. “What’s going on is that these procedures are impacting the emotional aspect of memory.”
“It’s easy to imagine how this could be used in a treatment setting,” he adds, in that it’s not only practical, but cost-effective—it’s designed to only be used once, or a few times at most. While this area of research is so young, it’s also got a lot of potential, Saladin believes. “We’ll learn more in the next decade, but even before then, we’re going know a lot more about potential treatment.”
Barak thinks rapamycin, which is FDA-approved to prevent organ rejection after a transplant, could be used as an initial treatment for cravings in alcohol addiction, but “if we can get the same or similar result without a drug, it’s always better.” With so few clinical studies, it’s hard to say what, if any, kind of side effects to these treatments there might be.
While much research in rats has shown that memory reconsolidation can be intervened upon pharmacologically, it was Elizabeth Phelps’ group at NYU, led by Daniela Schiller, who showed that in humans, reducing fear memories could be effected by psychological means, not using drugs. In a well-cited study from 2010, the lab showed that human patients who had been conditioned to fear a blue square on a computer screen could be re-trained to not fear the blue square if they were cued with a “reminder” 10 minutes before the usual fear extinction training. And, they were much more apt to not see their fear spontaneously come back—as often happens. In fact, the difference between the test groups persisted a full year on. It’s a new type of learning, says Saladin, compared to simply making memories extinct. “When you open that window [of reconsolidation], you are updating the content of that memory.”
Phelps thinks that psychological intervention is something that can and should be focused on instead of using chemical interventions, like propranolol—she thinks the data is too messy and so far, most of it is in rodents and not humans. Importantly, memory reconsolidation is a natural process, one that’s happening whether or not we manipulate memories in the lab. “This is how your brain works,” she says. “The purpose of reconsolidation is to strengthen memories over time, and the second may be to update memories with new information at the time of memory retrieval—by understanding [this], we can take advantage of that [process].”
Non-invasive techniques to target the reconsolidation of craving memories are just beginning to be investigated. In a most recent study from 2012, Chinese scientists led by Lin Lu at Peking University in Beijing used a retrieval-extinction process similar to Phelps and Schiller’s to reduce cravings and relapse in heroin addicts. They showed that in abstinent heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions reduced heroin cravings one, 30, and 180 days later.
To be sure, this doesn’t erase memories. And, it’s still “science fiction,” Phelps warns. “It is really interesting and has great clinical potential, but we really aren’t there.” In other words, don’t get your hopes up; researchers have a lot more work to do. As with most things in life—and addiction—there will be no easy fix. Just because you take away cravings doesn’t mean that you don’t have to work hard at changing your lifestyle, your worldview, or both. Moreover, for many addicts, the inner work only begins when the intense cravings of early sobriety begin to subside—getting past cravings can teach addicts a lot about why they got sober, and how to stay sober.