MDMA rolls onto the psychotherapy scene as FDA greenlights Phase III clinical trial

Remember the commercial? This is your brain on drugs. One could hardly forget the stark image, the idea that using drugs literally fries your brain. And it’s true that the brain changes in response to drug use. How it changes depends on the substance, dose, frequency and duration, as well as on the factors surrounding and supporting its use or abuse. But not all the neurological changes have to be damaging. There’s a growing body of newly legitimized research on MDMA, which is often used as a recreational euphoric among club goers and at music festivals. In light of what we know, the FDA has just made a controversial decision to greenlight a Phase III clinical trial, using MDMA to treat PTSD.

The fact that it’s Phase III is important, because Phase III are the clinical trials designed to fine-tune the safety and effectiveness of a drug before it goes on the market. These trials have to be well-designed in order to draw any valid conclusions, and this particular study is under even more scrutiny because of MDMA’s presence on the Schedule 1 list of drugs with no acknowledged clinical value. Because MDMA has been “in the wild” for so long, there already exists a corpus of early research on its effects. Now scientists are applying for “breakthrough” status for its use in psychotherapy, on the premise that since it’s been around for a while, we know a good bit about its relative safety. What’s important, the logic goes, is quickly assessing its effectivity for “off-label” use to treat PTSD — which is sort of funny because normally it’s the off-label use that’s less legit.

It’s worth asking why a recreational euphoric is of any interest to clinical science at all. The answer is in the neurotransmitters. MDMA, also called “Ecstasy,” represents a profoundly different state of brain chemistry from the norm; upon dosing with MDMA, a flood of neurotransmitters including norepinephrine, oxytocin, dopamine and serotonin are released by the user’s neurons. The idea is, essentially, that psychiatrists can use small doses of MDMA to grab patients by their recalcitrant neurotransmitters, from where it can be a useful adjunct to talk therapy — allowing patients to re-evaluate past traumatic experiences in a safe environment, casting the trauma in a different light, and breaking the neuronal stalemate. It could take a consciousness-altering experience to penetrate a PTSD patient’s deeply entrenched response to trauma. Alexander Shulgin, upon encountering MDMA, sought not just to understand its euphoric effects but also to explore its use as an antidepressant-like aid to talk therapy. According to his seminal work, Phenethylamines I Have Known and Loved, the first thing he did was run to his psych-department and mental healthcare colleagues with the drug, to get it under their scrutiny, from where it became much more popular both in therapy and in the club.

An ecstasy tablet. Image: Wikipedia

But MDMA also has a reputation for danger. Recreational users frequently report to emergency rooms for major body-chemistry imbalances, including grave sodium depletion, called hyponatremia — which seems like it should just get a “eat chips and drink some Gatorade, n00b” until you realize that your neurons (your brain is mostly made of neurons, by the way) literally cease functioning when their environmental sodium concentration is wrong. Once a person’s neuronal function is compromised they may not be able to pick up on what’s wrong. There’s also an enduring but poorly substantiated expectation that MDMA in high doses can be excitotoxic, especially when the user is under high external stress — such as a loud, overheated club, when the user is exhausted, out of blood sugar and electrolytes, and possibly under the influence of other drugs. Rolling on molly, even once, can result in a brutal multi-day hangover related to the way it depletes serotonin levels in the brain.

This would suggest, even to the layman, that molly is at least transiently bad for your brain. But there’s a tide of conflicting user reports that high doses and frequent use are more responsible for any persistent damage than acute exposure. Furthermore, some long-term users report that taking precautions (“rolling smart”) and getting aftercare — e.g. supplements like 5-HTP, SSRIs, other neurotrophic drugs and even cannabis — can mitigate this effect. This suggests that science may be overlooking situational but tightly associated risks of MDMA, in favor of monitoring those we consider inherent to the drug itself.

The UK’s Dr. Andrew Parrott, a much-quoted researcher on MDMA abuse, writes (PDF) that most MDMA users are polydrug users – 90% use alcohol or cannabis, usually concurrently with MDMA. Alcohol abuse is an important confounder. Furthermore, Dr. Parrott remarks, some of the damaging effects of MDMA on heavy users “are consistent with the ‘energetic stress’ model for recreational MDMA users, where the adverse metabolic effects of MDMA are exacerbated by concomitant non-drug stimulation,” although he cites only his own work to support his assertions.

The outlawed status of MDMA means that nobody has yet put MDMA-using patients or volunteers in an fMRI, nor made a broad, longitudinal survey of long-term users’ brain development with CAT scans. With the ever-increasing sophistication of our medical imaging and brain mapping methods, it won’t be long before we can tell just what clusters of cells are being affected by drug use, and how that changes the flow of information through the brain. Big data can lend itself to comparisons between large groups of those who do and don’t use drugs like MDMA, to apply the power of statistics to the sample. Better understanding of what different drugs do to the brain will lead to better understanding of what to do about drug abuse.

In the end, people are going to seek out the recreational drugs of abuse they want to use, and witholding legal ability to do research on those drugs will not stem the supply. “The massive epidemic of casualties we were promised back in 1988 simply has not happened,” remarked Dr. Ben Sessa, a pioneering UK researcher on MDMA, rebutting Dr. Parrott’s works in a letter to the British Prime Minister. “Prof Parrott demonises the medicine MDMA because he sees –- quite rightly –- that the illegal drug Ecstasy has its risks. But recreational Ecstasy is not the same thing as clinical MDMA.”

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