When Jonathan Lubecky tries to pinpoint the lowest point of his life, he has a hard time picking one. There was the day in 2006 the former Army Sergeant came home from Iraq to find his wife gone, along with his dog and his motorcycle. “A bad country song,” he says.

Then there was the Christmas eve when Lubecky walked out of a Raleigh bar where he was trying to drown his nightmares, went to church, and was turned away. “They told me, ‘We’re full, come back in the morning.’ ” That led to his first suicide attempt. The last, of five, was November 4, 2013. “My wife and I had a fight, I blacked out, I found out later I slit my wrists,” Lubecky says. He ended up in a psych ward for six long days. Jonathan Lubecky was diagnosed with PTSD after a blast injury he suffered during a training accident. Less than a year after waking up in that padded room, Lubecky found himself in a Charleston, South Carolina, bungalow that serves as the office of Dr. Michael Mithoefer and his wife Annie, a trained nurse. The Mithoefers are a psychotherapy team leading a series of experiments testing the drug MDMA—better known as “ecstasy”—as a treatment for post-traumatic stress disorder (PTSD). Lubecky had been diagnosed with PTSD in 2006. In addition, a blast injury from a training accident had left him with memory problems and a deep depression. He’d sat through countless therapy sessions, but this one was different. It was his first experience with MDMA. His head was spinning, his eyes full of faint geometric patterns. His tongue, usually paralyzed when it came to talking about the war or his struggles, was untied. “What was interesting was that for the first time I was talking about these things, and I didn’t have a physical reaction,” he recalls. After just two sessions with the drug, Lubecky’s PTSD symptoms were virtually gone. His experience is typical of the two dozen people—veterans, firefighters, and police officers—in Mithoefer’s study. Dozens of people in Mithoefer’s studies—veterans, firefighters, police officers, and assault victims—were essentially cured after two sessions with MDMA. Prior to that, all had had moderate or severe symptoms and had tried conventional treatments to no avail. “It does represent this possibility that the medicine is a catalyst,” Mithoefer says. “If you can shift consciousness in a certain way, profound change can happen very quickly.” Modern Studies with MDMA and Psychedelics Change might be coming to the way the U.S. regulates the drug, too. On November 29, the U.S. Food and Drug Administration held a meeting that’s a big step towards a multi-center study in which MDMA is given to hundreds of patients with PTSD, the final stage before a new medicine can be approved for use outside of research. It would be a striking turnaround for a drug that’s been banned and vilified for more than 30 years. While not a classical psychedelic in terms of its chemical structure or effects, MDMA-assisted therapy is closely modeled on earlier work with LSD, mescaline, and psilocybin, the main psychoactive ingredient in “magic mushrooms.” Those drugs, too, are seeing a resurgence of interest in their use as medicine. A pair of studies just published by researchers at New York University and Johns Hopkins University found that psilocybin helped patients who were suffering anxiety or depression due to a life-threatening illness. Researchers in Switzerland reached similar conclusions in a study using LSD.

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The NYU team is a year into a study to see whether psilocybin can help alcoholics stop drinking, while other recent trials have tested the drug as a treatment for depression and obsessive-compulsive disorder, as a stop-smoking aid, and to reduce anxiety in adults with autism. Only a few hundred patients have been treated in this array of studies, but even cautious voices see a potential shift that could overhaul the practice of psychiatry. “It raises all sorts of interesting issues about neuroscience,” says Dr. Paul Summergrad, chair of the psychiatry department at Tufts Medical School and a former president of the American Psychiatric Association, who is not involved with the studies. “What are the neural circuits which underlie the way we organize our day-to-day thinking?” Psychedelics and the Brain The promise of sudden, dramatic personality change, what some liken to “psychic surgery,” is an intriguing feature of psychedelic medicine. LSD, psilocybin, and MDMA all clear the body in a few hours, but the user-experienced “trip” lasts several hours more. Residual effects can last years, if not a lifetime. Fundamentally, no one knows why this is. “If these drugs have demonstrable effective results in people who are otherwise not getting better from serious conditions, then the issue really becomes: how and why does that happen? What’s the mechanism?” Summergrad asks. In some ways, the action of psychedelics and MDMA are well known. All trigger a flood of neurotransmitters, notably the chemical serotonin. Essentially, the drug molecules mimic the shape of the serotonin molecule and are taken up by specific receptors in the brain. MDMA also causes the release of dopamine, norepinephrine, and oxytocin. But then what? It was once hypothesized that oxytocin—a hormone expressed by lactating mothers and thought to play a key role in bonding between mother and child—was vital to MDMA’s effects, perhaps by increasing trust between the patient and her therapist. But when therapists gave oxytocin alone to PTSD patients, they didn’t improve. Another molecule, serotonin, is closely associated with mood. The most popular class of antidepressants are selective serotonin reuptake inhibitors (SSRIs), which prevent the brain from reabsorbing the serotonin it produces, effectively increasing the level in circulation. Under the influence of MDMA, LSD, or psilocybin, serotonin levels spike but quickly return to normal as the drug clears the body in a few hours. And yet, the effects on mood tend to linger much longer, which isn’t the case which SSRIs, which must be circulating to have an effect. More revealing may be brain imaging techniques like functional Magnetic Resonance Imaging (fMRI), which measures changes in blood flow to different parts of the brain. As viewed with fMRI, psychedelics clearly change patterns of brain activity. One striking shift is in the circuitry of the default mode network , or DMN, a group of brain regions that generally work in tandem when the mind is not focused on a particular task. It’s thought to include areas generally associated with higher-level thinking. The study of depression carries a hint of how quieting the DMN might lead to beneficial treatments. In a depressed person, the mind tends to race, flooded with negative thoughts. Indeed, brain-imaging studies suggest that the default-mode network is overactive in people who are clinically depressed. If psilocybin or LSD can reduce DMN activity, it stands to reason that it might help those patients feel better. “People get locked into these very negative loops of thinking and feeling,” says Dr. Stephen Ross, an addiction psychiatrist at NYU who led the recent study on psilocybin. “It’s possible that by deactivating these kind of constrained circuits, you can disrupt it and reopen the person to another rhythm of thinking, perceiving, and behaving.” After giving subjects psilocybin, one team also found a dramatic decrease in blood flow to the medial temporal lobes, brain regions thought to be crucial to our sense of self as distinct from other objects or individuals. Changes resemble those seen in brain-imaging studies of experienced meditators and nuns engaged in prayer—forms of intense spiritual practice. Reversing the Fear Response An enduring question in the study of mental health is to what extent the changes a patient experiences are the result of new “thinking” as opposed to more primal shifts. One area of PTSD research focuses on the latter. The condition that nearly cost Lubecky his life, PTSD, can be viewed, on a very basic level, as a form of learned behavior. In the wake of a life-threatening incident or extended abuse, the patient “learns” to avoid stimulus that’s perceived as freighted with danger. Up to a point, this kind of conditioning is normal and crucial to evolutionary success. If you’re not afraid of saber-toothed tigers, you won’t last long. But with PTSD, conditioning goes beyond what’s healthy, and the brain overreacts to stimuli that do not, in fact, signal a threat. Common symptoms include hypervigilance, nightmares, shame and guilt, and a sense of being emotionless. Even a faint reminder of the trauma can evoke a strong physical response, like a panic attack. Severely affected war veterans or sexual assault survivors may avoid even small crowds, cutting themselves off from friends or even simple shopping expeditions. Some say avoidant behavior is at the heart of PTSD. For one thing, it’s self-reinforcing. “If people have an intrusive disturbing thought and then do everything they can to shut it down, that probably trains the brain that this is still a scary thing you have to avoid and run away from,” says Dr. Kerry Ressler, a psychiatrist and neuroscientist at McLean Hospital and Harvard Medical School. “Successful avoidance effectively reinforces the fear memory.”

“If people can be really engaged but not over-engaged or overwhelmed by emotion, that’s when the therapeutic change happens.”

Treatment often centers on the fear response. “You can look at recovery from trauma as a form of extinction learning,” says Ressler, who adds that the goal of therapy is to reconstruct neural pathways to disconnect a traumatic memory from its overwhelming emotional charge. In experiments at Emory University, Ressler’s base until last year, researchers were able to blunt the fear response in mice by giving the animals a low dose of MDMA. First, they trained mice to fear an electric shock, by delivering the shock in tandem with an audio tone. Two days later, they were de-conditioned, by having the sound played without the shock. During the latter process, some animals were dosed with MDMA; these mice grew less skittish during the de-conditioning process, while the drug-free mice remained fearful even after being re-trained. Matthew Young, who ran the experiment, says the mechanism isn’t clear, but he and Ressler say it may involve proteins like BDNF, short for brain-derived neurotrophic factor. Previous mouse studies by Ressler and his colleagues showed that BDNF within the amygdala could enhance fear extinction, or de-conditioning. MDMA, combined with extinction training, seems to trigger production of BDNF which in turn is thought to stimulate the growth of existing neurons, increasing what’s known as neuroplasticity, or the brain’s ability to change. Ressler says the findings suggest a biological basis for the improvements in patients like Lubecky. A longtime skeptic of MDMA therapy, he says, “this helps make me more comfortable that whatever [MDMA] is doing, it doesn’t depend only on the social relationship part” of a patient’s interaction with a therapist. Young left Emory this summer to work for a private pharmaceutical company, but his former colleagues are preparing a similar experiment in healthy human volunteers. (They’ll be “fear-conditioned” with short blasts of air to the neck, not electric shocks). He says it’s too early to draw conclusions. “The fear response is simple, but social behavior is tremendously complex.” MDMA-Assisted Therapy MDMA-assisted therapy, like the work with psilocybin, draws heavily on lessons from the LSD era, such as the importance of setting. Patients spend most of their time lying down, with eyeshades, including long stretches of silence. “The Mithoefers didn’t direct me, but they helped,” explains James “CJ” Hardin, an Army veteran who was treated in the Charleston study. “If I started losing my train of thought or if they saw that I was processing something, it just kind of helped me to stay on point. Like, ‘You said this, so let’s talk about that.’ ” Even without prompting, trauma always comes up, Mithoefer says. Most patients can discuss experiences that previously were overwhelming. “There’s something that’s been described in other kinds of therapy called the ‘optimal arousal zone’ or the ‘window of tolerance,’ ” he explains. “If people can be really engaged but not over-engaged or overwhelmed by emotion, that’s when the therapeutic change happens.” Dr. Michael and Annie Mithoefer are a psychotherapy team leading a series of studies on the use of MDMA as a treatment for PTSD. While this explanation has an intuitive quality, it seems to conflict with more established methods for treating PTSD, in particular a widely used approach known as prolonged exposure (PE), or simply exposure therapy. Patients are coached to identify a particularly traumatic memory; the therapist helps them develop a script that they work through repeatedly, until the sting of the memory—and the physical sense of panic it evokes—is numbed. “Over time, it gets easier,” says Dr. Barbara Rothbaum, director of the Trauma and Anxiety Recovery Program at Emory University and a prominent practitioner of exposure therapy. “It’s about modifying our stories. There’s something powerful about saying out loud our worst moments and having another person who’s trying to help hear it.” “The presumed component is reactivating the memory over and over again, sitting with it, and habituating to it,” says Ressler, “In neuroscience terms, you’re extinguishing that memory. You’re re-training the brain so that these sets of memories and cues aren’t threatening anymore.” Memory, Emotion, and the Senses Exposure therapy is based on the premise that effort and struggle—directly facing the pain of trauma—are vital to healing. Making it easier to talk about might seem counterproductive. But there’s evidence that isn’t true, at least not for everyone. Unlike a computer hard drive, where individual packets of information are recalled, unchanged, memory is more like a cherished recipe. Each time we experience memory, our brain essentially retrieves the ingredients and mixes it from scratch. It meshes concrete facts with sights, sounds, smells, and emotions, often linked to other memories. The kitchen where the cooking takes place, so to speak, is the brain structure known as the hippocampus, which also plays a key role in processing sensory information, and in our emotions. Simply put, Matthew Young says, “You remember emotional experiences better than non-emotional experiences.” Emotion, in turn, is tied to our senses. “There’s a lot of anecdotal evidence that things like sense and sound are especially important in bringing about traumatic memories,” says Sarah Mennenga, a neuroscientist at NYU who works with Ross. Dr. Bessel van der Kolk, a prominent therapist and trauma expert in Boston, says patients with PTSD don’t feel like they’re remembering their trauma; they’re constantly reliving it, in a jumble of fear, sensory overload and a distorted sense of time. Just look at their brain scans, he says. “You don’t see trauma in the cognitive part of the brain. It’s in the very primitive parts, the cockroach brain.” Scans of patients with PTSD show a shift away from activity in areas associated with higher-order thinking—like the prefrontal cortex—and towards regions implicated in emotion, like the amygdala, what Mithoefer and others refer to as the brain’s “fear center.” Psychedelics, meanwhile, are well known for sensory distortions. Users often report seeing breathtaking geometric patterns, or synesthesia, the mixing of the senses that can include “hearing” colors or “smelling” music. It’s not a stretch to think the drugs might shift stubborn patterns of thinking, by shifting sensory components that are intertwined with fearful memories. While MDMA, psilocybin, and LSD don’t all hit the same brain receptors, “the downstream effects are not that different,” Mennenga says. “They’re all things related to neuroplasticity.” Van der Kolk considers the MDMA research promising, but also wants more research on mindfulness training, yoga, and what he calls body-based therapies. “Anything that makes you viscerally feel safe can be a good treatment,” he says, by giving the mind the rest it needs to heal. That echoes what CJ Hardin recalls about the first time he took MDMA—in a quiet setting with friends, after coming home from the war but before starting treatment. “For the first time, I felt safe, happy, free, and it was like a weight had been just immediately lifted.” Spiritual Healing The notion that a single dose of any drug could produce profound healing has powerful appeal, and Mennenga explains how it might work. “Theoretically, if you were to break down all these associations temporarily—anxiety, emotion, cues in the environment—that would change the direction in which things go in the future,” she says. “Even if the immediate neuroplastic effects are gone, that would result in an entirely different trajectory of learning and memory for that person”—a butterfly effect in the brain. Of course, that’s likely true for any powerful, awesome, or gut-wrenching experience, including trauma itself. But studies show clearly that psychedelics can produce life-altering feelings. In a trial at Johns Hopkins University with healthy volunteers, most participants reported that taking psilocybin was among the five most meaningful experiences of their life. “It goes back to spirituality and meaning,” Summergrad says. “An experience of oneness, purpose, holiness, sacredness, these things are very powerful, and in these studies they seem to be highly correlated to people’s improvement. You have to ask what this says about the power of these states as part of human experience and about what we think of as mental health.” In a more familiar realm, the path of discovery continues. Some scientists are asking if psilocybin or LSD might help with depression by tamping down inflammation in the brain . Others are preparing experiments to see if MDMA could be used in tandem with more conventional treatment; Barbara Rothbaum is planning a study next year that will combine MDMA with exposure therapy. No one knows if the early successes will be repeated. “The history of mental health treatments is littered with things that look good at first, but eventually don’t turn out to be so helpful,” Summergrad warns. But Jon Lubecky, who went on to graduate from the Citadel after his treatment and now works as a writer and political consultant on veterans affairs, says it’s time to find out. “When you have 20 veterans a day killing themselves, and many others who aren’t vets, we really have to do something more than we are now.”

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Photo credits: Caleb Hellerman, NYU