Scientists Are Trying to Make Fear Extinct

There’s a lot to be afraid of these days. Maybe you can’t find a job in this sputtering economy and it’s gnawing at your pocket and existential well-being. Maybe you just heard about that horrible shooting in _____. Maybe you just found out your government has the capability to track every word you type.

Or maybe you’re a recently returned veteran—or a drone pilot—and you’re afflicted with PTSD, perhaps the most tragic manifestation of pathological fear. If you are in this minority, however, or if you know someone who is, you can take some solace in knowing that more brain researchers are working to understand the physiology of this affliction. And they hope, eventually, to eliminate it.

In the last few decades, neuroscientists have made great progress in mapping the circuitry within a region of the brain called the amygdala, which regulates a process called “fear learning” involved in PTSD. Consequently, there’s an ongoing effort to use this growing body of knowledge to inform the way patients that suffer from pathological fear receive treatment. This often involves cultivating the process opposite fear learning, which scientists call “fear extinction.”

Researchers study the mechanisms of fear by testing rats’ abilities to learn to associate ordinarily neutral stimuli, like beeping noises, to unpleasant stimuli, like electric shocks. When researchers condition rats to expect a shock upon hearing beeps, making the beep a “conditioned stimulus,” fear learning is said to have taken place. Likewise, when they learn to dissociate the conditioned stimuli with the shocks, called the “unconditioned stimuli,” this is evidence of fear extinction.

Nesha Burghardt, a postdoctoral researcher at Columbia University College of Physicians and Surgeons, recently explained the process in the journal Biological Psychiatry. “Extinction does not destroy original fear memories,” she wrote, “but instead involves learning new information about the relationship between the [conditioned stimulus] and the [unconditioned stimulus].” For a soldier returning from war, for example, an IED going off in a marketplace is one such relationship—fear extinction occurs when the soldier can finally dissociate going to Trader Joe's from explosions.

A series of recent studies may illuminate where there may be success, or not, in developing treatments that encourage fear extinction. One such study, led by Dr. Burghardt, implicates long-term SSRI use in the obstruction of fear extinction learning. SSRI, which stands for “selective serotonin reuptake inhibitor,” is a class of antidepressants that functions by allowing the neurotransmitter serotonin to stay bound to receptor cells for longer periods of time. Neurotransmitters binding to receptor proteins on neighboring cells is a crucial element in the communication between cells. It dictates the functioning of the nervous system, and a greater duration of time bound often translates to more pronounced effects. Prozac, perhaps the most famous antidepressant to date, is an SSRI.

Dr. Burghardt’s study showed that when rats were treated with an SSRI called tianeptine, it drastically altered their capacities for fear extinction. Rats that received short-term SSRI treatments—they got the drug for 9 days—developed a greater capacity for fear extinction. Conversely, rats that were treated for 22 days saw their ability to cultivate fear extinction become impaired.

Researchers also noted that in the group treated for 22 days, there was a decrease in the amount of a particular receptor protein largely affected by serotonin activity. This suggests that the protein, called the NR2B subunit of the NMDA glutamate receptor, is crucial in mediating the fear responses. Which means that the many people taking antidepressants for PTSD may be quashing their ability to successfully instigate fear extinction.

“These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning,” Dr. Burdghardt said. She suggests that “it would be ideal to develop a drug that selectively activates the NR2B subunit of the NMDA receptor in the amygdala, to facilitate extinction learning.” Such a drug would counter the SSRI’s unwanted effects on the receptor.

Dr. Alexander Neumeister, of the departments of Psychiatry and Radiology at New York University Langone Medical Center, supports the notion that we need new drugs to combat fear, but he is taking the search in a different direction. Dr. Neumeister, who studies PTSD, refers to “a consensus among clinicians that existing pharmaceutical treatments such as antidepressants simply do not work” for people with the disorder.

Dr. Neumeister’s suggestion does not reflect well on SSRIs, considering that they are a first-line treatment for the disorder. This is clearly problematic, especially because estimates have pegged the percentage of veterans returning home with PTSD at near 20%.

And while there’s still not even a concrete diagnostic procedure for PTSD, one of Neumeister’s recent studies is bringing the community closer to changing that. He’s working to highlight an objective biological irregularity in PTSD brains. His study, published in Molecular Psychiatry, found differences in the amounts of the neurotransmitter anandamide and its corresponding CB1 receptor in the brains of humans with post-traumatic stress disorder, as compared with their normal counterparts. PTSD patients had decreased levels of anandamide, which has long been implicated in mechanisms involved with learning.

Documentation provided by NYU Langone School of Medicine to accompany the study suggests that decreased anandamide levels belie the over-representation of the CB1 receptor, to which anandamide binds. Dr. Neumesiter believes increased expression of CB1 receptors are the result of compensatory measures that allow the brain to “utilize the remaining [transmitter]” if it should ever prove scarce, as it appears to do in cases of post-traumatic stress disorder.

Anandamide and the CB1 receptor are part of the endocannabinoid neurotransmitter system, named as such for their susceptibility to manipulation by America’s favorite illegal drug, cannabis, or marijuana. The structural and functional similarities between the endocannabinoid anandamide and regular cannabinoids like THC might suggest therapeutic uses for marijuana, a THC-rich substance, in the treatment of PTSD.

In fact, Dr. Neumeister said that “people with PTSD who use marijuana—a potent cannabinoid—often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications.” Of course, it’s still difficult to access legitimate medical marijuana in many parts of the country, so that treatment isn’t readily available to everyone.

Instead, SSRIs, some of which may actually exacerbate etiological underpinnings of PTSD, are prescribed almost by default. Granted, drugs of this class do have overall positive effects in many patients, and marijuana is not suitable as a replacement across the board—it’s an imperfect medicine, to say the least. Yet it’s increasingly clear that many patients are in a situation where they have to choose between de facto and de jure treatments that may both be flawed.

Finding a truly workable solution will require both changing state laws to accommodate medical marijuana users, and pursuing further research so more diverse treatments can at some point become available.

It seems like we live in a world of unending stress; for those afflicted by PTSD, it's more like a waking nightmare. Clearly, we need to find ways for the worst affected to cope. For them, the race to bring fear closer to extinction can't be won soon enough.

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