Calming the Anxious Brain

Could people with anxiety disorders be suffering because they’re not producing enough endogenous opioids—the brain chemicals best known as natural painkillers? 

Animal research has long suggested that if you prevent these neurotransmitters from acting, rats fail to become accustomed to initially frightening stimuli. Now, a new study published in the Journal of Neuroscience shows that the same thing happens in humans.

This could help explain why people with anxiety disorders and those who suffer childhood trauma have elevated rates of addiction to opioid drugs like heroin and Vicodin—and even suggests that such medications could potentially have a role in anxiety disorder treatment.

Here’s how it works: Ordinarily, if you pair a tone with an electric shock, a rat learns to fear the tone and expect the shock.  Over time, while the experience never exactly becomes pleasant, the rat eventually realizes that nothing dire is really going to happen and chills out.

If you give a drug that prevents the brain’s opioids from working, however, the rat never mellows.  In fact, his fear escalates and he becomes increasingly terrorized with each experience of the shock and tone. 

This is exactly what happens in people with phobias: Every time they see a snake or a spider or have to deal with crowds or heights, their fear spikes, rather than calming the way it does for unaffected people.

Scanning the brain

The new research involved 30 men, studied in a brain scanner.  They were shown pictures of triangles or pentagons—in half of the trials, the sight of one of the shapes was followed by a painful (but not dangerous) blast of heat to the forearm.  The other shape was always “safe”—no pain occurred when it was shown. 

Half of the men were given the opioid-blocking drug naloxone, the same drug used to treat overdose; the other half got placebo.

Both in terms of brain response and behavior, the men given the naloxone were more like the phobic rats: Although the other men got used to the heat, those on naloxone found it more aversive over time, not less so.

This could be seen in the amygdala—a brain area that processes fear—which continued to light up in the naloxone group after it had calmed amongst the others.

What this suggests is that brain opioids modulate our response to fear—they make formerly frightening situations tolerable, and they tell us everything’s going to be OK.

Consequently, it’s unsurprising that people whose lives have been marked by high levels of fear and threat, like child abuse victims or people with anxiety disorders, would be attracted to drugs that reproduce this effect—problems develop when a compulsive pattern of use occurs in which negative consequences outweigh benefits. People who have anxiety disorders are four to six times as likely to suffer from addiction as those who do not—and child abuse notoriously multiplies addiction risk.

Our opioid complex

Before the advent of modern antidepressant and anxiety medications, opioids were actually used to treat anxiety and depression with some effectiveness.  Now, however, fears about addiction have created a legal framework that makes such use wildly controversial.

This tends to prevent researchers from even studying the question, despite research finding that opioids can be used to treat chronic pain without causing addiction in the vast majority of cases and despite the successful use of maintenance treatments for addicts.

The new study’s lead author, Falk Eippert, a Ph.D. candidate at the Department of Systems Neuroscience at University Medical Center in Hamburg, Germany, notes that Andrea Kozak and colleagues at Northwestern University in Chicago have proposed studying opioids for use during “exposure therapy,” which is the most effective treatment for phobias. 

Unfortunately, because exposure therapy involves repeated encounters with the object of one’s terror, many patients cannot tolerate it. Consequently, something that could improve people’s ability to withstand exposure could be extremely useful in therapy.

Kozak has studied the use of the opioid-blocking drug naltrexone (which, like naloxone, has the opposite effect of opioids and can reverse overdose) during exposure treatment.

As you might predict from Eippert’s results, this backfired. Patients given naltrexone were less able to stand exposure treatment and their fear actually got worse over time.

So would giving opioids help?  Eippert says that a potential problem is the phenomenon known as “state-dependent learning.” What this means is that “subjects might learn to reduce their fear under therapy with opioids, but might not be able to use this strategy when drug-free.” 

This phenomenon has been documented with other drugs: For example, if you study for a test when you are high, you’ll be more likely to recall the material if you take the test high, as well. Your brain recalls the material better in context—if that context happens to be stoned, your recall of it will be better when you are also stoned. (Note: This is not meant as any sort of test-taking advice!)

If opioids reduced fear only during the exposure sessions and this didn’t generalize to real life, that wouldn’t be of much use.

But until someone does the research, we won’t know.

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Maia Szalavitz is a journalist and author who covers the intersection between mind, brain and behavior. She is a senior fellow at Stats.org , a media watchdog organization, which investigates coverage of science and statistics. Her own experience as a former heroin and cocaine addict brings a unique perspective to her work. She's a regular contributor to Brain & Body. Her most recent book, co-written with leading child trauma expert Bruce D. Perry, M.D., Ph.D., is The Boy Who Was Raised as a Dog and Other Stories from a Child Psychiatrist's Notebook: What Traumatized Children Can Teach Us About Loss, Love and Healing (Basic, 2007).