Even those who see promise in MDMA-assisted treatment aren't sure how it works. "It's not well understood by any means," said Mithoefer. "We think it gives people this window of time in which they can process things without being overwhelmed by emotion, but also not being numbed up."
He said brain imaging studies, while crude, support the theory that MDMA alters hard-wired connections between conscious thought and emotional reactions -- or overreactions.
"We do know that MDMA decreases activity in the left amygdala, and increases it in the prefrontal cortex" -- brain areas associated with emotion and higher thinking, respectively, he said.
David Nichols, a professor of pharmacology at Purdue University, said no one really knows why MDMA, as well as drugs like LSD and psilocybin, have such a profound effect on the brain.
"I liken it to rebooting a computer," he said. "But when it comes to things that change the fundamental structure of personality and consciousness, and changes who you are, we don't really understand that."
Nichols warned against a simple explanation. "You could talk about neurotransmitters, but that's really superficial. (MDMA) releases serotonin, dopamine, norepinephrine. It activates other hormones. But what does that all mean?"
'Why do we need this MDMA?'
Uncertainty is easier to take if you think there's no other option, and Foa argued it's a misperception that existing treatments are ineffective.
A recent study by psychiatrists at the National Center for PTSD tracked 171 patients who received either PE or CBT therapy. After 10 years, fully 80% still enjoyed milder symptoms. However, about one in four of those treated could not be found for followup.
"With PE, you get about 40-50% (cured) of PTSD, and you get about 80% getting improvement," said Foa. "So we have good treatments, that have no side effects. The question is, why? Why do we need this MDMA?"
Foa also cites concerns about neurotoxicity, although a 2011 study by Harvard psychiatrist Dr. John Halpern found that occasional MDMA use produced no cognitive damage.
Dr. Julie Holland, a psychiatrist who is overseeing the safety of an MDMA study Mithoefer is now conducting on veterans, said most risk is eliminated by the controlled nature of the experience.
For casual Ecstasy users, said Holland, "The biggest risk is not knowing what they're taking." Apart from being illegal, the street drug is often contaminated with other substances. Holland added that, "The next big one (risk) is heatstroke, if you get out and dance for six hours."
"The third biggest risk is overhydration," she explained. People are taught to stay hydrated, but MDMA causes the body to retain water. Combined with the drug's disorienting effects, this can lead users to overdrink, to a condition known as hyponatremia, a dangerously low concentration of sodium in the blood. "This is the main reason MDMA users die," said Holland, "from drinking too much water."
In a controlled setting, said Holland, "You get an incrementally higher heart rate, higher blood pressure and body temperature, but there isn't real danger as long as you're moderately healthy."
'Real people are paying the price'
Additional studies using MDMA against PTSD either have been completed, are planned or are under way in Colorado, Canada, Spain, Switzerland, Israel, Australia and Great Britain. Meanwhile, Mithoefer is conducting a study treating military veterans and firefighters; so far 11 people have enrolled and more than 280 have called to see if they might take part.
While the military and Department of Veterans Affairs have expanded services in recent years, they struggle to keep pace with the inflow of new patients. The number of active-duty military personnel seeking treatment for PTSD rose from 10,408 in 2002 to 281,468 last year, according to Cynthia Smith, a Department of Defense spokeswoman.
One reason MDMA seems tempting is the sense that existing treatments are not enough. "It's not like we don't have effective treatments for PTSD," said Dr. Boadie Dunlop, director of the Mood and Anxiety Disorders Program at Emory University. "But there are many people for whom these therapies don't work."
Retired Brig. Gen. Loree Sutton, who headed the DOD's Centers of Excellence for Psychological Health and Traumatic Brain Injury from 2007 to 2010, said she left the Army in part because she felt existing treatments often do more harm than good.
"We invested in conventional approaches towards research, but I also knew we had to go beyond that," said Sutton. "Real people are paying the price for our failure to harness knowledge."
The National Center for PTSD, a branch of the VA, says approved treatments include a type of antidepressant known as SSRIs (selective serotonin reuptake inhibitors), along with EMDR, CBT and PE, developed by Foa. In some studies, more than three-quarters of those who complete PE therapy are "cured." But success can be hard to evaluate, in part because treatment is too emotionally painful for many patients to complete.
The DOD and VA also support a variety of research, much of it to try to fine-tune existing approaches. For example, Foa is leading a study offering more sessions in a shorter amount of time -- twice weekly -- to soldiers at Fort Hood, Texas. About 360 people are expected to enroll.
Neither the VA nor the military is part of clinical MDMA research, but Sutton said that before leaving the Army, she did call Rick Doblin to encourage his work. Doblin is the founder of MAPS, the Multidisciplinary Association for Psychedelic Studies, which wants to turn mind-altering drugs like Ecstasy into prescription medicine.
"With MDMA -- Ecstasy -- if rigorously designed studies show there's a benefit, better than existing therapies, then we should use it," Sutton said.