The Agony and the Ecstasy: The Quiet Mission to Fight PTSD With MDMA

Michael and Annie Mithoefer's patients come to their clinic in Charleston, South Carolina, as a last resort on a grueling tour of duty. Unable to shake what they've experienced, witnessed or carried out, on orders or otherwise, in the suburbs of Baghdad or the valleys of Helmand Province, they're wracked by the relentless mental sirens of post-traumatic stress. They've sought out the husband-wife team because no other therapy has made it all stop. They're up for anything.

The Mithoefer's are upfront: should trauma not surface at the patient's behest, well, then at a certain point they'll make it surface. The process can be painful, and spans hours, so patients arrive mid-morning. After final "set" preparations each subject is handed one small, curious capsule. It's 10am and they're ingesting ecstasy.

The daylong sessions that follow are part of a small, open-label Phase II study of MDMA-assisted psychotherapy for post-traumatic stress disorder in war veterans. The experiment examines how 3,4-Methylenedioxymethamphetamine, better known as ecstasy, may alleviate the crippling, long-term horrors of "chronic, treatment-resistant, combat-related PTSD" when administered at low doses and in controlled settings.

This is the leading edge of a 10-year, $10 million push by the Multidisciplinary Association for Psychedelic Studies for Food and Drug Administration approval of MDMA as prescription medicine. For now, the Mithoefer's score MDMA from the only licensed dealer in the US, a Purdue University chemist.

They're doled 30-, 75-, and 125-mg capsules from the only government-approved batch of ecstasy ever made, in 1985, when the drug was criminalized. (This product is routinely tested for purity, and remains over 99 percent pure MDMA.) This current study is double blind, so no one's privy to the dosage—125, 75, or 30, the low-level active placebo—they're taking from the outset of their trips. Then again, it's not too difficult to put a finger on just how hard you're rolling on ecstasy.

Once medicated, patients are encouraged to lay back, to focus inward. Some opt for eyeshades and headphones. Others simply close their eyes, favoring the quiet. Everyone waits.

What we know as PTSD isn't anything new. Severe, sustained psychological anguish stemming from harrowing experiences is an ancient phenomenon, though it was only first recognized in 1980 in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III).

The symptoms of PTSD are wide ranging. They fall under three broad categories, according to the National Institute of Mental Health. Re-experience symptoms are textbook pangs—vivid flashbacks, dark thoughts and darker dreams. Avoidance behavior includes shying away from "places, events, or objects" linked to the experience, plus emotional numbing, feelings of guilt, depression and anxiety, loss of interest in "activities that were enjoyable in the past," and even difficulty recalling the event. Hyperarousal sparks short fuses—one is easily startled, feels tense or "on edge," has difficulty sleeping and has sporadic, angry outbursts.

We're all subject to this at any age, science says. But in the United States we're breeding the disorder within the military at staggering rates. Over 70,000 veterans received PTSD disability support in 2005. One study, as the Economist reported in 2008, "estimated that 12 percent of American veterans from the wars in Iraq and Afghanistan suffer from PTSD." Last year, The New York Times figured "well over" 300,000 troops had returned with PTSD, depression, traumatic brain injury, "or some combination of those."

Distressed veterans and active-duty troops can take antidepressants like sertraline (Zoloft) or paroxetine (Paxil), the two FDA-approved SSRI (selective serotonin reuptake inhibitor) medications for adult PTSD. (Under a recent settlement between veterans and the military and stemming from a 2008 class-action lawsuit, more than a thousand Iraq and Afghanistan veterans with the disorder would be given lifetime disability retirement benefits such as military health insurance.) The FDA says these are relatively safe, but warns of unintentional side effects: "worsening depression, suicidal thinking or behavior" and "sleeplessness, agitation, or withdrawal from normal social situations." One recent study claims those on antidepressants are "much more" prone to relapse into major depression than the non-medicated.

Benzodiazepines—relaxation and sleep inducers that may meddle with memory and spur dependency, such as Xanax—"other antidepressants," like fluoxetine (Prozac) and citalopram (Celexa), or antipsychotics are all other medications the NIMH cites as possible PTSD treatments.

The military's medical program has over the past decade developed a knack for throwing prescription drugs at the mental health problem, so much so that the Army now limits how many addictive painkillers any soldier can acquire at any one time. It's not uncommon, though, that troops be on multiple approved antipsychotics, antidepressants, and opiates simultaneously. The risks of overmedicated war machines hoarding drugs and channeling a "national psychosis," as some have illustrated, can be as unsettling as the original problem.

Between 2006 and 2009 over a hundred military personnel have died accidentally due to toxic prescription-drug blends. Illicit self-medicating, the default for so many Vietnam-era troops, is falling out of favor among newer veterans. Now, vets are five times more likely to abuse pills and alcohol than weed or coke or heroin.

The Government Accountability Office also just concluded that the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, created in 2007 when Congress tasked the Pentagon with establishing a program for handling influxes of brain injuries and PTSD among veterans, has no idea what it's doing.

The DCoE was supposed to be a guiding light when it came to developing techniques for treating so-called invisible wounds. But as Denise Fontane, who headed the audit, told NPR, "[DCoE was] not able to explain to us in any clarity what they're about, what they intend to do in the future, how much it's going to cost and what value will come out of that spending."

It may be unsurprising, then, to learn that suicide rates across the Department of Defense rose by about 50 percent between 2001 and 2008. Nor is it surprising that active-duty suicides topped battlefield casualties in 2009, or that a dozen reserve soldiers killed themselves last March, or even that some experts, according to the Times story, consider exposure therapy (a form of cognitive-behavioral psychotherapy) the "only proven treatment" for PTSD.

To its credit, the US Department of Veterans Affairs requires veterans seeking treatment be given universal access to prolonged exposure or cognitive processing therapies. But given the severity of the problem, it's hardly shocking that there's actually a waiting list of subjects eager to see about the Mithoefer-MAPS MDMA method.

MDMA's effects typically manifest themselves 30-45 minutes after ingestion, so it doesn't take long for rhythms to develop in Charleston. Sessions at the clinic oscillate between stretches of silent, inward focus, where the patient is left alone to process his trauma, and unfiltered dialogue with the co-therapists.

"It's a very non-directed approach," Michael Mithoefer told me. This allows subjects to help steer the flow of their trip. They are as much the pilots of this therapy as their overseers. "Once they get the hang of it," Mithoefer explained, "sometimes people will talk to us for a while and then say, 'OK, time to go back inside. I'll come report when I'm ready.'"

That said, patients understand that if no traumas emerge, the Mithoefer's must coax them out. But they've never had to. The traumas always emerge, and by now there have been over 60 sessions between an initial, smaller Phase 2 study and the present trials. Horrors are bubbling up naturally, patient after patient.

The Mithoefer's don't admit just anyone. Their protocol outlines precise inclusion and exclusion criteria. Participants must have been resistant to past medicine or psychotherapy treatment and have a Clinician-Administered PTSD Scale (CAPS) score of 50 or above. (Considered the "'gold standard' in PTSD assessment," according to the International Society for Traumatic Stress Studies, CAPS is a 30-60 minute interview structured to exhibit categorical diagnoses and measures of symptom severity as defined in the DSM-IV.) Active substance abusers and those with psychotic disorders or type 1 bipolar disorder are rejected. Certain conditions, like hypertension, depression and other anxiety disorders aren't an issue, though Mithoefer said applicants must be "relatively medically healthy."

So far, all those meeting criteria are enrolled. "We don't pick and choose," he said. Locals may take priority, though, as it's cheaper working with people from the area. But they've accepted people from across the country.

Vital signs are monitored throughout sessions. Blood pressure and pulse rate are measured every 15 minutes. Body temperature is recorded on the hour, at which point subjects reliving experiences, alone and inside, are checked on. Intense emotions and visuals are commonplace, so preventing freak-outs is critical. There's even space at the clinic for patients to spend the night, which they're required to do.

If the thought of returning to the unthinkable isn't enough, imagine your most horrific life experience stroked, possibly for the first time, by MDMA. "It's painful," Mithoefer admitted. "A few people on the first day have said they don't know why it's called ecstasy."

Psychoactives offer new access to deeper regions of the brain, according to Amanda Feilding of the Beckley Foundation, an Oxford-based charitable trust using modern brain-imaging technology to explore consciousness and its altered states. Experientially, they seem to purge the repression that prevents attention getting to trauma. This reduces treatment length from years to hours, in some cases. Therapeutic psychedelia, Feilding said, "is a great, beautiful orchard filled with ripe fruit for picking."

From out of this beautiful orchard, replete with LSD and psilocybin, ibogaine and cannabis, MDMA seems especially equipped to enhance psychotherapy. "MDMA has the greatest opportunity of any psychedelic to be integrated into psychiatric practice," MAPS founder and director Rick Doblin wrote in "A Clinical Plan for MDMA."

Ecstasy is brief, for one. Compared with, say, LSD, whose effects can last in excess of 10 hours, MDMA's roughly four-hour "primary effect" window (and two-hour comedown) is relatively manageable. Ecstasy is also gentle despite its slight toxicity, which can cause depression in the days following trips. Compared to acid, which warps "rational cognition processes" and perception and may also prompt fear and panic, MDMA operates more so on emotions than cognitive function. It subdues the amygdala, the inner-brain "fear center" that sparks heavy negative emotions, while opening serotonin and dopamine brain-messenger floodgates and boosting blood levels of oxytocin and prolactin, two sociable hormones.

In other words, patient-therapist empathy increases. Patients are comfortable, all things considered. They're willing to enter "the eye of the trauma," as Feilding put it. In this regard, she argues, MDMA's not unlike psilocybin insofar as it "removes the filters," allowing people to consider situations past and present in slightly different ways.

The subjects are in the sweet spot. Mitheofer says so many people are resistant to PTSD treatment because of either under- or over-engagement. He and his wife, a psychiatric nurse, are observing that MDMA shepherds subjects into an optimal arousal zone, or window of tolerance. It's here that they can connect with their emotions while revisiting trauma and not lose it, so to speak. "Four or five hours in this zone," he said, "may be what gets them past the obstacle to treatment."

That doesn't mean it's easy. But it's not overwhelming—or free from all uncertainty.

"I have concerns," said Charles Hoge, a psychiatrist and senior scientist at the Walter Reed Army Institute of Research. Hoge spent two decades on active duty before signing on at the Office of the Army's Surgeon General and Walter Reed. And while he hasn't delved too deeply into the medicinal-psychedelic literature—"I don't know much about it," he admitted—Hoge noted that MDA (3,4-Methylenedioxyamphetamine) and its related compounds have significant, immutable biological effects.

"They have irreversible bindings on some receptors in the brain," he explained, "which can potentially result in maybe greater or longer-term side effects for an individual." SSRIs, he claimed, are reversible.

Whether long-standing regulations can be overturned is another question. The policy push for FDA approval is not easy. It's overwhelming. "We're in a dark age at the moment," as Feilding put it. Yet she believes we're on the brink of a sort of renaissance in which psychedelia's medicinal potential is fully realized, accepted by the old guard of global-medical politics after decades of staunch resistance.

The current Mithoefer-MAPS trials just enrolled a sixth patient, and will cap at 16. Brad Burge, MAPS' director of communications, said that's a low enough figure that the study is manageable, but high enough to yield statistical significance. Burge admitted that it would be better to have 100 subjects—any significant result would then carry some real weight.

"But we actually have a lot more than 16 waiting to be interviewed by the research team," he said, and will "almost certainly" have enough subjects for Phase III. "We're not terribly concerned about that considering how prevalent PTSD is, and how enthusiastic so many people are about trying these new therapies."

"This is already mainstream research," Burge added, given MAPS' collaboration with governments and universities from around the world. (He may have a point, considering Oprah's nod.) "We're already doing this just like a mainstream pharmaceutical company would do it," he said, so it's "pretty clear" prescription MDMA for PTSD psychotherapy will be available at the corner store within the next 10 – 15 years. To him, it's a question of when, rather than if.

So the Mithoefers will roll on. In addition to ongoing trials, they're following up with participants from the initial Phase II trials, which used inactive placebos. (The researchers noticed a "big improvement" from sessions where patients took placebos to those on ecstasy. These results were the most downloaded article from the Journal of Psychopharmacology in 2010.) Three years later, how are they feeling?

Eventually a paper will be published on this, though for now the co-therapists are wary of sharing data. But they told me that average CAPS scores weren't fluctuating wildly—an encouraging sign. Yet a few people relapsed.

"They were having significant symptoms again," Mithoefer said. "The benefit didn't last for everyone, but the benefit did last for a majority of people."

Still, SSRIs are the only Level-A medications to have been shown in randomized trials to be "fairly consistently" effective for treating PTSD, Hoge insisted. He added that a lot of newer-class antipsychotics are being developed with fewer and fewer negative side effects; there are even adjunct medications that may help treat certain PTSD symptoms. Prazosin (Minipress), a blood-pressure medication with no psychotropic effect, has been shown in a few randomized trials to dampen physiological hyperarousal, especially in reducing nightmares, which then encourages improved sleep.

But as with MDMA and all other ripe fruits of the great, beautiful orchard—"all those types of things"—until prazosin and various other promising medications are tested more rigorously in randomized trials with double-blind control, "we can't confirm whether they're effective or not, whether they have greater side effects or not," he said. "I think that's the bottom line."

Of course, the effects and promise of various PTSD drugs mean nothing when many of those most in need of treatment are reluctant to seeking treatment in the first place. Writing in an editorial that ran with a study published last week in the Journal of the American Medical Association, Hoge not only suggested that a whole class of antipsychotics, including Risperdal, Seroquel, Geodon, and Abilify, can't top placebos. He points to the bigger, more pervasive problem: Half of veterans who can't shut out the mental sirens, and who should seek care, don't.

The quiet stigma of PTSD has helped turn the post-apocalyptic illness into a cross-generation epidemic, and amplified its already devastating effects.

There are many reasons for the "don't ask don't tell" approach to PTSD, and not all are unique to the military. Some people fear being shunned by their peers or leaders or potential employers. Others run up against barriers to treatment—it may be difficult to land an appointment, or individuals may choose to prioritize work over getting help. Others simply have the idea that mental care doesn't work, that it's a shoddy "last resort," Hoge told me. And among those who do manage to begin treatment for PTSD with either psychotherapy or medication, he wrote, "a high percentage drop out," typically between 20 and 40 percent, a figure that can rise "considerably higher" in routine practice.

Meanwhile, Michael and Annie Mithoefer and others continue to fight a guerrilla war against PTSD, special forces in the shadows. "We're encouraged by the results so far, but we have to do a lot more research, and it'll be interesting to see how it all unfolds," he said.

But progress isn't just a matter of breaking taboos—and amending regulations—around psychedelics and other edgy treatments. Medicine may not win the war on PTSD until society can break much more basic taboos, around the terrible, invisible traumas of combat. Only then might veterans have a chance to trade the bitter pill of war for one that only tastes bitter.