dance with the devil. That’s how 33-year-old Elizabeth Mooney describes her struggle with drug addiction, recalling the “little voice” that repeatedly overpowered her mind after she had been in recovery, once for as long as three years. She knows the consequences of using again, yet she’s relapsed five times.
The desire became “stronger and stronger and stronger,” she said.
The opioid epidemic ravaging the United States has brought new impetus to understanding how addiction hijacks the brain. More and more, scientists are shifting their focus to what’s going on in the brain after people like Mooney go off drugs.
Their quest has unveiled a troubling picture: Repeated drug use leads to long-term changes to the brain. Some of those changes, new research suggests, might be hard to reverse and might even intensify right after withdrawal, explaining why it is so hard to stay off drugs.
“We have to realize they are unable to maintain abstinence not for lack of desire but because their brain is damaged,” said Eric Nestler, a professor of neuroscience at the Icahn School of Medicine at Mount Sinai and one of the country’s preeminent experts on the molecular basis of addiction.
All addictive drugs cause an unnatural surge of dopamine, a brain chemical that’s normally released upon rewarding activities like eating, having a nice conversation with a friend, or kissing a loved one, and this then drives an individual to repeat that activity. But the drug-fueled dopamine surge is not enough to cause addiction. There is something about repeated drug use that changes the brain at a deeper, more permanent level.
A multitude of studies in animals have found numerous genes and proteins whose production is altered in the addicted brain when compared with normal brains. Human imaging studies have confirmed this notion of a reprogrammed brain.
The science points to new strategies for developing therapies that might reverse the brain changes, and it’s bolstering an increasingly accepted view of addiction as a chronic disease that must be managed like any other illness.
“Like diabetes and cancer, you’re in remission, but sometimes that disease comes back and you have to go through that process of recovery all over again,” Mooney said. Now in recovery for two years, she works at the Massachusetts Organization for Addiction Recovery, pairing addicts with services to help them.
Her journey started with a doctor prescribing opioids for nine months to relieve pain after a “horrible” car accident when she was 20; she had broken ribs, bruises, and a concussion. It almost ended in 2015 after a heroin overdose.
“I was going to work every day … and getting high in the bathroom,” she told STAT. “Looking back, that’s just insanity.”
Reprogramming the brain
The question is, how do the long-term brain changes begin? One way, scientists are now learning, is that the brain seems to be drawing upon a specialized set of tools, known as “epigenetic” mechanisms, to cement its drug-linked reprogramming.
These molecules alter the activity of genes in ways that are enduring and widespread — like turning off the water main of a house instead of individually closing all its faucets. Some are enzymes that add or remove chemical tags in proteins or DNA, others are small strings of genetic code that block protein production. Epigenetic mechanisms are used by cells and tissues to create stable changes, such as when an embryonic cell changes into a heart cell.
It makes sense for epigenetics to play a role in addiction, and these changes would help explain why addicts can relapse long after not having drugs in their system. “Certainly for years after being abstinent, they can suddenly get an uncontrollable motivation to take the drug,” said Peter Kalivas, chair of neuroscience at the Medical University of South Carolina. “That always seemed to us to be the result of some enduring change, or a vulnerability left in the brain by the repeated use of drugs.”
A study published this month in the journal Biological Psychiatry found widespread epigenetic alterations in the brains of heroin addicts. The research, led by Yasmin Hurd, director of the Center for Addictive Disorders at Mount Sinai, found changes in one type of epigenetic mechanism called histone acetylation, which affects how DNA is packaged in the cell. The more histone acetylation, the less compact the DNA is, making genes in that region more accessible to being turned on.
Hurd’s team analyzed an area of the brain, called the dorsal striatum, which plays a strong role in compulsive behavior. The brains of deceased heroin users had much higher overall acetylation than brains from non-addicts. Along with the epigenetic changes came higher activity in a cluster of genes related to the neurotransmitter glutamate, which is known to play a role in drug cravings and risk of relapse. The longer an addict had used heroin, the higher the levels of gene activation.
Another study of epigenetics looked at a well-established phenomenon in addicts called incubation of drug craving, whereby cravings are triggered by certain cues — which could be a smell, or a street sign, or any object that the addict associates with drug use — and get stronger the longer an addict has been off drugs.
The researchers trained rats to use cocaine in the presence of a cue, such as a light or a sound, so that they desperately sought the drug if they saw the cue. This drug-seeking behavior became even more intense 30 days after the rats were taken off the drug.
When the researchers examined the rats’ brains — specifically, the so-called “reward” area where dopamine is released — they found that cocaine withdrawal triggered major changes in levels of DNA methylation, an epigenetic mechanism that cells deploy to keep genes turned off. Also, the light or sound cues that triggered addictive behavior caused a spike in methylation alterations, and the longer the rats were in withdrawal, the higher the number of genes with methylation changes.
Moshe Szyf, a professor at McGill University’s medical school and one of the authors of the study, said the insights have implications for the treatment of addicts as they go through detox. “When people withdraw, and supposedly they’re in a rehab and kind of free of drugs, the brain is not really free of thinking about drugs,” Szyf said. Immediately after withdrawal, and for a while thereafter, “the epigenetic processes are ongoing.”
Studying cravings during abstinence is of utmost importance, said Kalivas, because “that’s actually what’s shared behaviorally with all addictive drugs: this overwhelming motivation to get the drug. It causes you to ignore your kids or work.”
Kalivas has been studying how a cue — for example, a lever that releases food or water for a research animal — is turned into an action, namely the pressing of the lever. The neurotransmitter glutamate plays a key role in this process.
Typically, when an animal or a person sees a cue (the lever) associated with a reward (food or water), about 1 to 3 percent of neurons in the reward area of the brain get activated by glutamate to drive the behavior (the pressing of the lever). But in addicted animals, Kalivas has found that glutamate signaling is in hyperdrive and recruits about 18 percent of the neurons to drive drug-seeking behavior.
“So basically, something’s happened that causes a much larger piece of this pathway to be devoted to the seeking of the drug,” he said.
Kalivas has studied cravings in addicted rats up to six weeks after withdrawal, and the 18-percent effect endures, he said. Extrapolating to human addicts, the findings provide an explanation for why addicts relapse in spite of dire consequences.
Inside the brain, the drug-related cue “supersedes the other stimuli and you basically make the wrong choice,” Kalivas said. “You almost don’t have a choice because that has become so powerful.”
That’s a compulsion Mooney knows well. “I even said it to myself at times: This is a red flag,” Mooney recalled of the thoughts that led her back to using drugs. She remembers fighting with herself to get back on track, “but it’s so overpowering.”
Can we heal an addict’s brain?
With all the new research on addiction comes opportunities for therapies that may one day reverse the condition. Developing drugs to treat addiction has been notoriously hard, and not just because of the science. Unfortunately, the stigma surrounding the disease has kept the pharmaceutical industry, and investors, at bay.
“When I started this work 30 years ago, I would always tell people that we expected to develop new treatments within five or 10 years, and it’s 30 years later,” said Mount Sinai’s Nestler, whose lab is trying to catalog epigenetic changes that occur in the brain during chronic drug addiction. “It’s been extremely difficult.”
Kalivas’s team has been able to reverse drug-seeking behavior in addicted rats using a compound called N-acetylcysteine, an antioxidant that has been used for decades to treat acetaminophen overdoses, and which is believed to interfere with glutamate signaling. “A five-day regimen of this drug and that all goes back to normal,” he said.
N-acetylcysteine can be purchased in stores as a dietary supplement and has been widely studied in clinical trials for a variety of mental disorders such as PTSD, and addictions such as gambling. According to Kalivas, results in addiction so far “get mixed reviews.”
His group recently published a small study of the compound in 35 veterans with PTSD and substance abuse disorder, who were given either the drug or placebo for eight weeks. The amount of craving was reduced by 81 percent in the N-acetylcysteine group compared to 32 percent in the placebo group, and the frequency of craving was reduced 72 percent with the compound, compared to 29 percent in the placebo group.
Agents that interfere with epigenetic mechanisms are another set of obvious drug candidates to treat addiction. In the study by Szyf, rats were treated with a drug that inhibits DNA methylation. “After 60 days they were not addicted even though they were treated once,” Szyf said. He is cofounder of a Montreal startup that is using epigenetics to develop diagnostic tests and has marketing rights to an experimental addiction treatment.
At Mount Sinai, Hurd’s team treated heroin-addicted rats with a molecule that blocks the effects of acetylation. The molecule, called “bromodomain inhibitor JQ1,” made the rats significantly less interested in heroin, and also reduced relapse after they had been off heroin for over one week.
“The potential of such an approach both for opiate and other addictive disorders is inspiring,” wrote Yale psychiatrists Drs. Brian Fuehrlein and David Ross in a commentary that accompanied Hurd’s publication. The JQ1 molecule has completed Phase 1 clinical trials in cancer.
The emerging evidence linking epigenetics to addiction is intriguing, said Elliot Ehrich, chief medical officer at Alkermes, a biotechnology company that makes Vivitrol, the only drug approved by the FDA to prevent relapse from opioid addiction. In clinical trials, addicts reported reduced cravings when they were on the medication.
Given the company’s focus on addiction, and its interest in understanding cravings, Alkermes is studying the changes that occur in brain cells in the hopes of developing better treatments, Ehrich said.
“Can we use our existing tools or add on other tools to give patients an option to heal their brain?” said Ehrich. “That’s the holy grail, but we are not there yet.”
In the meantime, Mooney wants addicts to know that healing is possible, with a lot of work and vigilance. She’s focusing on spending time with her family and “learning to find the true meaning of what happiness to me is. Like finding the gratitude in the little things,” she said. “There is hope out there.”