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Staying Cool With Glutamate

By Jeanene Swanson 03/10/14
Can an over-the-counter supplement now becoming popular for mental health and mood elevation help a person stay sober? The early research is promising.

Most addicts will tell you that it’s easier to get sober than it is to stay sober. And, the more we learn about the neurobiology of addiction, the more addiction treatment specialists are inclined to say that relapse is a part of recovery.

Do addicts have to “white knuckle” it in order to get sober and stay clean? Yes, replacement and anti-craving medications exist, but many still suffer from generally poor outcomes. Replacement therapies for opioid addiction, such as methadone and buprenorphine, and for nicotine addiction are widely accepted. Alcoholics have naltrexone and acamprosate. However, all these are substance-specific, which is a disadvantage to using them to treat addicts who have more than one substance use disorder. Also there are no FDA-approved medications for treating addiction to cocaine and other stimulants. 

Peter Kalivas, a professor and researcher at the Medical University of South Carolina, has been studying the role of glutamate—a ubiquitous excitatory neurotransmitter in the brain—in addiction for over a decade. He believes that addicts can’t learn how to improve or alter their behavior because their substance use has actually impaired a critical brain circuit involving glutamate, one that allows them to translate the desire to change into action.

He’s not alone. The glutamate homeostasis hypothesis of addiction has not only gained traction in the lab in the past 15 years, but in the past five years, hundreds of clinical trials have ramped up with a focus on attempting to heal those damaged glutamate circuits using NAC. NAC, or N-acetylcysteine, is a precursor of the naturally occurring amino acid cysteine, and it is one particular compound that has shown immense clinical promise in treating all sorts of disorders, but especially compulsive ones like addiction. NAC is not found in food, but when taken as a supplement, it breaks down into cysteine and then, glutathione—a powerful antioxidant. What’s more, cysteine is essential to maintaining optimal levels of glutamate.

You might have seen NAC at your local Whole Foods, in fact—it’s a common supplement. It received FDA approval in 1963, and has been used since to treat symptoms of bronchitis, COPD and Tylenol overdoses, among many other diverse, off-label uses. It has gained attention in recent years as scientists learn more about its role in addiction—and preventing relapse.

Preliminary clinical studies have shown the promise of NAC in terms of safety, tolerability, and potential efficacy for encouraging abstinence from cocaine, nicotine, and cannabis. There are hundreds of clinical trials underway in the US studying NAC in the treatment of various disorders, including addiction to alcohol, cocaine, marijuana, nicotine, and methamphetamine, and for behavioral addictions, namely gambling. And, with trials underway for Alzheimer’s and Parkinson’s diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder—well, it makes NAC one of the most promising drug candidates in neuropsychiatry.

Glutamate homeostasis

A growing body of research has linked changes in the glutamate neurotransmitter system to addiction. When addicts use, they deplete this chemical, which is essential for transmitting signals from the cortex to the nucleus accumbens. The cortex can be thought of as the decision-making center of the brain, while the nucleus accumbens—which is also involved in the dopamine circuit—is the habit area. In addicts, this circuit becomes weak at best, broken at worst. “Even though they know it’s bad, they can’t use this information to change their behavior effectively,” Kalivas says. Because they can’t update their “habit” in response to different instructions from the cortex, they keep on using despite their own better judgment.

The glutamate system maintains a balance of synaptic—between two neurons—and extracellular—outside of neurons—glutamate via a few different ways. One is an “exchange” molecule, which maintains an optimal level of glutamate inside and outside neurons; another is the number of receptors themselves. In any case, when levels of glutamate become off-balance, addictive behavior trumps so-called reason: cravings and relapse result.

A number of research studies have implicated glutamate dysfunction in addiction. In a 2002 study, David Baker, then at the Medical University of South Carolina and now at Marquette University in Wisconsin, found that repeated administration of cocaine in rats lowered glutamate levels. A paper the following year showed that these changes underlie relapse in cocaine users. In 2009, Kalivas published a study in rats that showed treatment with NAC re-activated stalled glutamate pumps and restored glutamate levels to normal. In 2011, he found that NAC treatment not only restored synaptic plasticity, but that it could be tied to less relapse behavior in rats. 

“When glutamate transmission is in balance, we can learn; when it’s out of balance, we can’t learn,” Kalivas says. This is called synaptic plasticity, and in addiction, this flexibility of our brain circuits to adapt to change all but dries up. 

NAC—on trial

While the FDA approved NAC for treating specific conditions unrelated to addictive disorders over 50 years ago, some recent preliminary clinical trials suggest that NAC could be useful in the treatment of many other disorders, including SUDs.

Kevin Gray, also a professor and researcher at the Medical University of South Carolina, led the first randomized controlled trial for treating marijuana addiction, and they published their results in 2012. The trial involved cannabis-dependent adolescents, and participants received either 1200 mg NAC or a placebo twice daily throughout the 8-week treatment. They found that those who received NAC had more than twice the odds of achieving marijuana abstinence—reflected in “clean” urine drug tests—than those who received placebo. It is important to note that subjects received traditional behavioral treatment along with their dose of NAC.

“Given the controlled nature of the trial, we feel it reflects a real effect of NAC in enhancing response to behavioral treatment,” Gray says. “It targets one of many factors involved in addiction—nobody has, to date, tested whether it could work as a standalone treatment. For now, the evidence indicates that it is a helpful complement to psychosocial [or] behavioral treatment.” His group is currently conducting a follow-up study of sorts, across multiple sites and spanning 12 weeks, to test how NAC affects treatment success of cannabis-dependent adults.

Clinical trials for using NAC to treat relapse in cocaine addicts have also shown promising, albeit mixed, results. This is important because currently, there are no medications to treat cocaine and stimulant addiction. In a trial published in 2013, researchers tested the effect of NAC on treating cocaine addicts. The study, led by Robert Malcolm, also at MUSC, found that among users who received either 1200 milligrams NAC, 2400 milligrams NAC, or a placebo on a daily basis over the course of eight weeks, only subjects who were already abstinent had longer times to relapse and lower cravings if they were taking the 2400 milligrams. This suggests that NAC may be useful in preventing relapse among cocaine addicts who have already gotten sober, says Kalivas, who was involved with the trial study. In fact, they’ve already begun a trial along these lines. 

Not a cure-all 

To be sure, a supplement like NAC isn’t going to be a cure-all. As Kalivas says, “cure is a little strong of a word.” NAC works by ultimately increasing the amount of glutamate available to neurons—and, the more glutamate, the better signal transmission and the easier it becomes for addicts to break habits and learn new behaviors. “Basically it resets synapses and so they now have the opportunity to learn.” And while it may enable recovery, it won’t make any difference if an addict doesn’t change his lifestyle.

Trials have focused on determining the efficacy of using NAC in conjunction with traditional therapies, not as a replacement. “The reason for this whole line of research is the limited—[even] poor—abstinence outcomes with existing psychosocial [or] behavioral treatments,” Gray says. “We see NAC as a strong candidate for safe pharmacological augmentation of psychosocial treatment for substance use disorders.”

While he and others prescribe it to their patients “off-label,” some specialists are reluctant. “I don’t prescribe it since it is not FDA approved for this indication and there hasn’t been a large clinical trial to prove its efficacy yet,” says Khaled Moussawi, previously at MUSC and now a neurology resident at Massachusetts General Hospital, who has done research himself on glutamate and its role in addiction. “All the data we have are preliminary.” And, unfortunately, some don’t see FDA approval in the future: “There will never be FDA approval because why would a company go to those lengths when the supplement is available in every health food store in the country?” says Jon Grant of the University of Chicago, who led a recent trial for using NAC to treat obsessive hair pulling, a condition known as trichotillomania.


NAC can be purchased at any health foods store, but…you might want to consult with your doctor before starting to “pop” any pill, even an antioxidant supplement. According to multiple sources, it seems safe; however, there can be side effects, even if they’re relatively benign: nausea, indigestion, headache, and abdominal pain. It has been suggested that NAC may increase excretion of trace minerals; some evidence, however, suggests that this effect is too minimal to make a real difference. Nutritionists would suggest that individuals taking NAC for an extended period of time should also consider taking a multivitamin supplement.

Oral bioavailability of NAC has been shown to range from a mere 4 to 10 percent. It typically comes in 600-milligram capsules, which is much lower than the doses given in most of the clinical trials—it doesn’t necessarily have to be delivered orally, but that’s what’s safest and available to consumers at the moment. Given those two facts, it might not work at all.

There can be dangers to taking too much of it, as well as with other medications. According to the University of Maryland Medical Center, recommended adult doses of NAC vary depending on the health condition being treated; however, very high doses (more than 7 grams) of cysteine may be toxic. UMM also advises against drug-drug interactions. If you are being treated with medications that suppress the immune system (azathioprine (Imuran), cyclophosphamide (Cytoxan), or prednisone (Deltasone)); nitroglycerin and isosorbide (Isordil), two medications commonly used to treat chest pain; oxiconazole (Oxistat), an antifungal medication used for athlete’s foot; or activated charcoal; you should not use cysteine supplements without first talking to your doctor.

Jeanene Swanson is a regular contributor to The Fix. She last wrote about mental disorders and addiction.

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Jeanene Swanson is a science journalist who specializes in mental health and addiction. As a science writer with a background in biotechnology, she enjoys turning complex subjects into stories that everyone can understand—and apply to their lives. You can find Jeanene on Linkedin.

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