NAC: The Amino Acid That Turns Psychiatry on Its Head

One of the most intriguing things to me in psychiatry is the push-pull between specific diagnoses and common factors. Are all psychiatric disorders basically the same or are they radically different from one another?

For instance:

• Is schizophrenia different from bipolar disorder? And if so, how?
• Is major depression different from panic disorder? And if so, how?

The way diagnoses are made in the DSM-5 (Diagnostic and Statistical Manual, 5th edition) generally gives the impression that each disorder differs from the others in precise ways: A major depression is diagnosed by a person having five or more of nine symptoms for two weeks or more; whereas panic disorder requires four or more out of a dozen other symptoms.

So, if you only have four depression symptoms, you can’t be diagnosed as having major depression. And if you only have three panic disorder symptoms, you don’t have that diagnosis. Fair enough: You have to draw the line somewhere. But is your four-symptom depression or three-symptom panic really different than that of the person who has the full number of required symptoms?

Complicating matters is this: Many people "meet criteria" for having many DSM-5 psychiatric diagnoses at once. You can have panic disorder and major depression — along with social anxiety disorder and specific phobias. Then the question arises: Do you have two, three, or four different problems? Couldn’t your several diagnoses all result from a single problem in your brain, a set of circuits or brain centers with abnormally increased or decreased activity that cause either a few or a lot of symptoms?

This may seem like an almost theological dispute, similar to the question of the number of angels dancing on the head of a pin.

But in the real world, it’s not at all trivial. Should you ignore one of the diagnoses—say, panic disorder—and only treat the depression, you’re likely to have a worse outcome than if both conditions are addressed. Yet, similar treatments often work for both conditions. Both SSRI medications and cognitive behavioral therapy (CBT) help depression and panic disorder, though the treatments may need to be customized for each disorder.

On the other hand, some treatments help one condition and not the other. Bupropion is a powerful antidepressant, but not very effective for panic disorder, whereas lorazepam, a benzodiazepine, helps panic disorder but may be counterproductive in depression. On the third hand, so to speak, if you could identify common circuit problems that underlie a wide range of psychiatric disorders, maybe you could find a single treatment that could help a wide variety of problems. On the fourth hand, there’s the possibility that people with one diagnosis—say, major depression—may have any number of different circuit abnormalities, just as your fever of 103 may result from a wide range of bacterial or viral infections, or a host of other causes.

Lumpers vs. Splitters

Psychiatry is thus like many other fields: with contending bands of lumpers and splitters. Extreme lumpers contend that there is only one dimension of psychopathology (Caspi). Extreme splitters point out that PTSD from combat differs from PTSD from violent assault, which differs from PTSD from sexual assault, and that each one benefits from different treatment approaches.

What does neuroscience have to say? Over the last decade or so, thanks to an initiative sponsored by Thomas Insel, M.D., Ph.D., the former Director of the National Institute of Mental Health, researchers have hopscotched over this controversy by focusing on brain circuits. The Research Domain Criteria (RDoC) initiative of 2008 focused research on identifying brain circuits that may go awry in many different disorders, common abnormalities that may underlie many different conditions.

Overall, the research on brain circuits generally gives support to lumpers: It’s generally the same circuits that go awry in nearly all psychiatric disorders, though perhaps with different emphasis for different disorders.

Which gets me to N-acetylcysteine.

N-acetylcysteine, or NAC, is an over-the-counter compound that can be purchased at your local health food store. As with dozens if not hundreds of other compounds, NAC has its devotees and detractors, its enthusiasts, and skeptics. (And I’m generally a skeptic of the herbal/supplement industry products).

Psychiatry Essential Reads

What to Know Before a Loved One Is Hospitalized

Cannabis Legalization Impacts Use of Psychiatric Medications

NAC is an amino acid, something present in many foods, but supplements give you a higher dose than you’d get in your daily diet. It is usually taken in doses from 1000 to 2000 milligrams per day—usually in 600-milligram capsules taken 2 to 3 times a day, and other than mild gastrointestinal side effects NAC is usually well tolerated. [Note: Suffice it to say, you should talk to your doctor before taking this or other supplements to see whether they are suitable for you. In my psychiatric practice, I view a trial of NAC as similar to any other drug (or therapy) trial: You need to get a patient to an adequate dose for an adequate period of time, and carefully measure its effects on key symptoms (and monitor side effects) over a long enough duration to be able to conclude whether it’s helping.]

[ALSO PLEASE NOTE: the use of NAC for psychiatric symptoms is an off label use. The only FDA approved indication for NAC is in treatment to prevent serious liver damage from acetaminophen poisoning. As such, if you are planning to use NAC for psychiatric or other medical symptoms please discuss with your physician to make sure it is safe and potentially beneficial]

The intriguing thing about NAC to me is that it’s of great interest to neuroscience researchers. There have been many studies of this compound, including neuroimaging studies, and it has been investigated in innumerable disorders—depression, bipolar disorder, OCD, PTSD, schizophrenia, addiction, eating disorders, Alzheimer’s disease, and addiction (Berk). NAC also has established medical uses as an anti-inflammatory medicine in cases of acetaminophen overdose in preventing liver failure. Clinical trials have been promising in many (but not all) disorders where it has been studied (Berk). Clearly, there’s a need for more research studies, both more clinical trials in different disorders, and more basic research to see how NAC works in the brain.

Why does NAC help many people with psychiatric diagnoses? Why does it work across so many conditions? This is the intriguing thing, in my eyes. Are its benefits a result of its anti-inflammatory effects? Or some other mechanism? On a clinical level, in day-to-day work with patients, NAC seems to help with ruminations, with difficult-to-control extreme negative self-thoughts. Such thoughts are common in depression and anxiety disorders, and also in eating disorders, schizophrenia, OCD, etc. I’ve seen it help patients with such disorders when many other things, medicines or psychotherapies, have not helped much.

NAC doesn’t always work, but when it does, troubling irrational thoughts gradually decrease in intensity and frequency and often fade away. Negative thoughts (e.g., “I’m a bad person," or “Nobody likes me”) or ruminations about other people (“Will that girl like me?”) or about health issues (“Do I have AIDS?’) that can’t be quieted by reasonable evidence to the contrary, and that keep intruding on one’s awareness hour after hour, day after day despite all rational efforts to control, seem to diminish. Or, if they continue to occur, they are less distressing, and can be observed from more of a distance, with less worry or fear, and are less likely to trigger depression or other negative effects.

Which gets back to the longstanding debates between psychiatric lumpers and splitters. Do the benefits of NAC support the lumpers more than the splitters? Do they support the RDoC enthusiasts who are eagerly researching brain circuits? I think, in a way, such results do favor the lumpers. The improvement of irrational, difficult-to-control negative thoughts with NAC treatment in so many disorders makes it hard to avoid the conclusion that some common underlying circuitry is involved.

On the other hand, it’s not yet time for the splitters to go home conceding defeat. NAC doesn’t work for everyone, for one thing. But also, if the circuitry for ruminations is the same, why do some people with presumably hyperactive rumination circuits develop OCD and others develop bipolar disorder? And others yet, despite having severe ruminations, do not meet criteria for any psychiatric disorder? It’s possible that abnormal activity of particular brain circuits, starting early in life, may lead to the development of various different disorders over time, depending on your life experiences, coping patterns, etc. But how and why do their effects differ so much from one person to the next?

To me, the debates between the lumpers and the splitters are most useful when they help move science—and treatment—forward. In this case, with the emergence of NAC as a potentially beneficial treatment for a common symptom of many disorders, the goal posts are being moved usefully down the field.