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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.

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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.

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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.”

Matt Ganem, a former addict, explains the excruciating process of opioid withdrawal. Alex Hogan/STAT

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.”

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  • Vivitrol is only mentioned in passing, but it is truly close to being a miracle drug. The point of this and oral versions of Naltrexone is to reprogram the addicted brain to no longer associate the drug taking behavior with the reward of having its opioid receptors stimulated. I take oral Naltrexone an hour before I drink and when I do take a drink, there is no fun in it, just the other usually unnoticed effect of alcohol being a CNS depressant. This approach has caused me to cut my consumption to less than a fourth of what it was, but I have to drink to get the effect! Abstinence while on Naltrexone doesn’t work, because there is no association created between drinking and a lack of pleasure.

    Similarly heroin addicts will have to continue to take heroin while on vivitrol, as horrible as that sounds, so that their brain pathways will stop associating injecting heroin with getting high. It goes against our usual understanding and the attitude that abstinence is the only way forward, but Naltrexone can eliminate the cravings, something that nothing else can do. Everything else eventually fails and the person relapses.

  • the effects of drugs are never good.my husband was an addict for 10 years. this got him rehabilitated twice and sometimes in trouble.i almost gave up on him until he got prayed for by diviner peterson, who helped in getting him free from addiction.i got to contact him after i saw a testimony of a lady on this blog who also faced similar issue with her son until he got prayed for. now my husband is free from addiction and is being the best husband and father to our kids and i i’d urge anyone on this blog facing similar or any problem to also contact him via email:newgracefoundation@gmail.com

  • I found this article hopeful. Having a child that is a heroine addict, been through two detox yet has relapsed so many times I’ve lost count. Suboxene is just a gateway for an addict in my opinion. Getting into a Rehab is impossible for an addict who has no money and county health insurance. I’m watching my child slowly die. I hope through this article a lot more good will come forward.

  • With the scientific understanding of addiction & relapse especially with opioid isn’t use of suboxone, an opioid, without short term appropriate medical management necessary or are we fueling this epidemic & violating hipocratic oaths!

  • I think it is necessary to go back to the genesis of the addiction. It is my experience that those of us who are addicts (albeit in recovery for 30 years) not the result of falling into this subsequent to medically prescribed opioids became so as the result of wanting/needing to change our reality even temporarily to escape pain. I read recently about service members in
    Vietnam . The number of troops who used drugs on a regular basis during their deployment was astoundingly high, but most, upon returning home discontinued their use. How does this information comply with the research on epigenetics? I wonder if the plasticity of the brain might not be more applicable (“the neurons that fire together wire together”). I and other addicts I know in good recovery have virtually no urges to use, and no triggers seem to affect us. We have, essentially, rewired our brains. If there were some permanent epigenetic DNA changes, it would seem that this is not possible.

    • I agree with that,
      “wanting/needing to change our reality even temporarily to escape pain”,
      I’ve seen a lot of people use drugs in order to escape pain, in my experience the people I know did it to flee away from emotional pain, and they started using all sorts of drugs that just made them forget all the pain and feel good if for a little while. That use changed to very frequent use to escape it for as much as they could, combine this with excessive alcohol abuse. When they tried to come off the drugs, they got hit hard and had extremely bad reactions to it that lead to very dangerous thoughts and actions.
      So they felt the need to either end their lives or use again; after failed attempts to end their lives and getting legally stuck in help facilities, and after using again and seeing everything around them fall apart because of their use, they tried to detox again, leading again to a hard path with dangerous mental thoughts and actions. It’s a vicious circle. I noticed the very real brain change/damage in these people. Also I noted that there is a gene in their family that was seen in other family members that also have some sort of addiction or even suicide thoughts, in whatever form it may be. It’s hard to see loved ones go down that path. They have a genetic predisposition I noticed and there didn’t seem much anyone could do about it to help, and I now know that they can’t necessarily do anything about their addictive and destructive behavior, it seems be inborn and add in the drug use => permanent brain damage . I’m at that moment in time where either they relapsed and/or eventually they take their own lives. I hope that one day there will be a “cure”.

  • Interesting. I wonder whether the changes described here are a result of drug use itself .. or whether reward-seeking behavior plays a role in their development.

    Think of the effort your average heroin addict has to go through to score–find money, contact dealer, conduct illegal transaction, etc–and how much sweeter this makes the reward.

    I wonder, then, if drugs were more readily/trivially available (e.g. cheaply via legalized distribution channels), what effect this would have on these neurological changes.

    • Referring to repeated use results in long term changes and perhaps permanent brain damage which indicates to me abstinence aided by therapy and MAP is best way to go. Thus more funding for detox and treatment via tax on opioids at the pharma level.

    • A better source for treatment funding would be the savings realized by terminating the insane War on Drugs — the cause of decades of massive expense and human misery and, considering modern drug use rates, an abject failure besides.

    • What danger would that be? A significant reduction in the transmission of bloodborne disease? A 100% success rate in the prevention of on-site overdoses, even in the age of carfentanil? An increase in referrals to medical care, counselling and detox programs?

  • Very interesting and reliable article. If you are struggling against drug addiction then eliminate the words of give up from your life. You can only get rid of drug addiction with consistent efforts. However, if I talk about this article then it is full of interesting facts and figures especially references of researches are making it very attractive for keen readers.

    Flora Kohlmyer – Researcher at https://www.ashwooddrugrehabilitation.org/washington/woodinville/

  • Very interesting and encouraging article regarding, epigenetics. As an Addiction Counselor I am always looking for advancement in clinical research that transfers into beneficial therapeutic treatment.

    Thank you to all contributors to this article.

    Sincerely,
    Richard Schwartz

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