The Future of MDMA: Phase 3 and Beyond | In In Magazine | By By Russell Hausfeld

What does the future hold for MDMA? This is part 1 of a 4-part series on the future of MDMA. The series explores the Multidisciplinary Association for Psychedelic Studies’ (MAPS) ongoing FDA phase 3 clinical trials, rescheduling, health insurance, and the FDA program known as expanded access.

More psychedelic research is happening right now than at any other point in the last 50 years. The Multidisciplinary Association for Psychedelic Studies (MAPS) — a non-profit entity with a for-profit arm — has provided much of the funding and support for this research. They are now moving into unprecedented territory: Phase 3 trials for Food and Drug Administration (FDA) approval of MDMA-assisted psychotherapy.

Even in the 1950s and 1960s, when psychedelics began being studied in earnest, none had reached a point where they were this close to potential prescription.

Needless to say, the future of MDMA has a lot resting on MAPS’ Phase 3 trials. Recruitment for Phase 3 volunteers was officially announced November 29, 2018. The announcement stated that the research will take place at 14 sites and enroll between 100 to 150 volunteers with severe PTSD.

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Phase 3? What about Phase 1 and 2?

To better understand the significance of MDMA making it this far, let’s take a brief moment to observe the trajectory of MDMA — a drug first synthesized by Merck Pharmaceuticals in 1912.

Unaware of its potential uses, nothing of note was done with MDMA until the 1970s when psychiatrists began using it in conjunction with their psychotherapy practices.

The Drug Enforcement Agency (DEA) made a move to criminalize MDMA in 1984. But, in the 30-day public comment period before it was scheduled, Rick Doblin — the founder of MAPS — and other concerned citizens approached the DEA office with documentation of under-the-radar MDMA therapy testimonials.

“They didn’t realize there had been teams of underground psychedelic therapists and researchers who had been doing this for years, preparing for this day,” Doblin said.

Doblin ended up receiving and winning a hearing — the judge recommended that MDMA be Schedule 3. But, the DEA rejected the recommendation and made it a Schedule 1 drug, instead. There were lawsuits that ensued in appeals court, but these cases were eventually lost.

“It was clear the DEA was going to make this illegal and the only way we were going to make it back from this was through research in science and medicine through the FDA,” Doblin said.

“So, I started MAPS in ‘86.”

Six years and five rejected protocol proposals later, MAPS finally got a break from the FDA. They received permission to work with Charles Grob on Phase 1 dose response studies. As MDMA became more closely associated with the rave scene in the 90s, Grob — thinking MDMA was too controversial — began studying psilocybin.

After Grob’s departure, MAPS began work with PTSD in Spain, and eventually received approval for Phase 2 MDMA studies in the United States in 2004.

Doblin said they learned many lessons during Phase 2 trials, which ended in 2016 with a total of 107 participants. They learned that MDMA works regardless of the cause of PTSD. Whereas, the only other drugs approved for PTSD — Zoloft and Paxil — don’t work as well in combat-related PTSD cases.

Some also say that Zoloft and Paxil do not work as well in men as in women and that MDMA could be helpful with this. But, this claim has been refuted as an artifact of the relatively few men who were enrolled in the clinical trials for Zoloft and Paxil.

They also learned that patients who received lower doses of MDMA did worse than groups that received full doses and placebos, Doblin said.

“To our surprise, we also found that low doses — while they were sufficient to produce a more effective blind — tended to make subjects anxious and uncomfortable, feeling emotionally activated but still not quite able to suppress their fear responses to their trauma,” Doblin wrote in MAPS’ 2017 Summer Bulletin.

The results between full doses and placebos were pretty staggering, though.

After three therapy sessions with MAPS therapists, the placebo group of treatment-resistant PTSD sufferers had a 23% success rate of treating PTSD two months after the last session.

Adding in MDMA, the results are 61% successful within two months of treatment.

The important question for Doblin was: “Is this just a psychedelic after-glow?”

But, it turned out that a year after treatment, the successful results actually increased. 68% of the group no longer had signs of severe PTSD.

“So, what’s going on,” Doblin said. ”Is a process has been started that continues on its own to develop, and people continue to get better.”

The Phase 2 research also proved that you can reliably administer MDMA safely: in study settings, nobody overheats, nobody dies from drinking too much water, nobody commits suicide. Doblin said one day somebody might commit suicide, but it hasn’t happened yet. The FDA has told MAPS that a suicide would not be the end of the road for MDMA research, because they are working with a group of people who are already more likely to commit suicide.

MAPS presented all of their information to the FDA in 2016 and were approved for Phase 3 trials of MDMA-assisted psychotherapy for PTSD treatment. As part of this approval, MAPS received a legally binding agreement letter that requires the FDA to approve MDMA-assisted psychotherapy for prescription if the Phase 3 protocol, as designed, obtains statistically significant results and no new safety concerns arise. Whether or not politics will interfere remains to be seen.

“Considering that tens of millions of people have been taking MDMA for more than 40 years, we already know the risk profile very well. So, the key factor is whether we obtain statistically significant results,” Doblin said. “Even that is fairly assured since we will conduct an ‘interim analysis’ by an unblinded data-monitoring committee to review the data when 60% of the results are in. If we need to add more subjects to obtain statistically significant results, we will be told that.”

After 32 years, Doblin is finally moving MDMA into Phase 3 testing. And MAPS is approaching these trials with “breakthrough therapy” status no less. This means that the FDA will be working closely with MAPS to ensure that trials will be completed as efficiently as possible.

In preparation, MAPS has trained 84 therapists — 42 male-female therapy teams — and raised over $26.7 million dollars to fund the studies.

“We are ready to go,” Doblin said.

What happens if MDMA is approved for use?

MAPS is hoping to get their MDMA approved as a Schedule 3 drug by the DEA, which could happen if their results in FDA trials are successful. But, if you are under the assumption that MAPS’ success would mean MDMA will get rescheduled across the board, you’ll be disappointed.

FDA is only required to approve MAPS’ specific GMP (Good Manufacturing Practice) MDMA. GMP MDMA is a highly purified drug in a specific delivery system (currently capsules with certain amounts of MDMA and other inactive ingredients like sugar to make all the capsules weigh the same), according to Doblin.

General MDMA is the same active drug, but not made in an approved lab or necessarily ingested through a pill form.

“Even if general MDMA is rescheduled, only GMP MDMA from MAPS (manufactured by Onyx Pharmaceuticals and encapsulated by Sharp Packaging Services) will be available for purchase by prescription,” Doblin said.

Jag Davies, the Director of Communications Strategy for the Drug Policy Alliance, pointed out that simply rescheduling MDMA won’t change any kind of criminal penalties associated with the drug.

“There are lots of drugs that are approved for medical uses, yet still harshly criminalized,” Davies said.

If MDMA is approved for medical use, MAPS’ Public Benefit Corporation (MPBC) — the sales arm of MAPS, which Doblin describes as “refugees of Big Pharma” — comes into play. MPBC is a for-profit entity that will have no shareholders, other than the MAPS non-profit.

MPBC is in place to sell MDMA and to do new research — all the taxable stuff. Ultimately, the goal is for MPBC to become more self-sustaining, so that the non-profit side of MAPS can invest more funding into things like harm-reduction and education.

MPBC is currently working with ethicists at the University of Pennsylvania to develop a scorecard for determining other public benefits the company will work towards achieving.

Specific areas they are focused on include “respect for persons, radical transparency, justice and fairness, and democratic deliberation,” according to Merete Christiansen, MAPS’ Executive Manager and Assistant to Rick Doblin.

“We’re hopeful that once the scorecard is finalized that it can be used as a standard for other organizations in the psychedelic space, as well,” Christiansen said.

Amy Emerson — the Executive Director of MPBC — explained on the “Here We Are” podcast that MDMA, itself, may not be all that profitable.

The drug is already off patent. In fact, MAPS has hired a patent lawyer to develop anti-patent strategies so that nobody can patent the use of MDMA. Doblin says this is in response to the for-profit ibogaine research he observed, starting in 1986, where people ended up suing each other over intellectual property.

While this may be the case, Doblin has, in the past, come out in support of some for-profit psychedelic drug development like Compass Pathways, who have filed psilocybin manufacturing patents. He sees for-profit ventures and billionaire investment as signs of progress in the psychedelic field.

“It’s a good thing, not a bad thing,” Doblin told HERB, “because it means we’ve ‘cleared out the political obstruction’ and ‘shown there’s a regulatory pathway’ to psychedelic medicine. This is just an inevitable part of the mainstreaming process.”

MAPS will probably start making money both through actual drug sales, and through training and certification of therapists and clinics, according to Emerson.

Once MDMA goes generic — five years after it is scheduled — other people can begin to offer their own training programs for therapists. But, before it goes generic, Doblin said, MAPS may be the only organization offering trainings. If other organizations are created by therapists who MAPS has trained, they will also be able to offer trainings based on MAPS’ methods.

“We will need to assure ourselves that trainings are in harmony with our method,” Doblin said.

MAPS is also working on creating Risk Evaluation and Mitigation Strategies (REMS) for MDMA-assisted psychotherapy. These are programs implemented after a drug has been marketed to manage serious risks associated with the product. The FDA can require REMS for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.

REMS — if patented — have been criticized for potentially delaying competitors from entering the scene. An article written by partners from Latham and Watkins law firm stated that patented REMS provide “the right to exclude others for 20 years from the date of filing from making, using, selling or offering for sale the patented method – longer than the statutory exclusivity period for the drug itself.”

MAPS is not planning on patenting their REMS or their treatment manual, according to Doblin and Emerson. But, as noted above, future therapists interested in using MDMA-assisted psychotherapy will be required to go through MAPS’ training program and be approved to work with patients for the first few years.

According to Emerson, MAPS will likely run some of their own clinics, too. These could take the shape of upscale psychedelic clinics, spas, and storefronts. Doblin anticipates that these could be a reality by 2021.

“There are 14,500 drug-abuse treatment centers in America…33,000 yoga and pilates centers,” Doblin said. “So, we think there will be thousands of psychedelic centers that we are going to roll out in the 2020’s.”

Doblin’s hope is to one day move past medicalization, and utilize MDMA as a tool in other contexts such as conflict resolution — on a global scale or just in couple’s therapy sessions.

Optimism aside, there are still issues of access and inclusion to be considered

MAPS is looking to be approved for expanded access — also known as “compassionate use” — from the FDA so that they can begin prescribing MDMA and opening clinics before it is officially rescheduled. A similar policy was recently passed into law by President Trump, called “Right to Try,” which allows terminally ill patients to access medications not-yet approved by the FDA.

“It is compassionate use,” Doblin said. “So, if you have a disease that nothing helps and there are drugs being tested for it — even before it is approved — on a compassionate basis, you should be able to get access to it at your own risk and at your own cost.”

Right To Try is not not without skeptics, though. Some include the American Cancer Society Cancer Action Network and nearly 40 other patient advocacy organizations. These organizations came together to write former House Speaker Paul Ryan a letter stating that, while they support patient access to unapproved therapies, the Right To Try bill does little to “effectuate policy change that would afford [their] patients greater access to promising investigational therapies.”

“When access to a therapy is denied to a patient, it is generally the [drug] company that denies the request, and for reasons that appear to be reasonable,” the letter states. “Such as a determination that the benefits do not outweigh the risks, an unavailability of sufficient product to offer outside of clinical trials, costs, or concerns about adversely affecting clinical trial enrollment.”

Expanded access clinics would have to be opened by or in collaboration with psychiatrists who have received MAPS training with MDMA: about 84 people throughout the country, currently. It is going to be a very small market in the beginning, which is often a detriment to affordability.

The Phase 3 MDMA treatment protocols call for 12 sober therapy sessions, with three MDMA sessions. In total, between 42 and 60 hours. Some estimate that this therapy could cost around $15,000.

Doblin says that this estimate is accurate for some clinics. But, others may deviate from protocol within limitations to potentially aid costs.

“Some PTSD patients will not need all three MDMA sessions. Some sites will not use overnight stays which can save some money (but I do think the overnight stays are ideal). Some sites will have two licensed therapists while other sites will have one licensed therapist and an unlicensed student working toward a license being paid much less than the licensed therapist,” Doblin said.

MAPS is also in communication with insurance companies about obtaining coverage for MDMA therapy.

Hopefully MAPS will find a way to increase affordability and access, but MDMA is already struggling to make it to a diverse array of people. There is currently a problem of representation within MDMA research. Of 107 participants in MAPS’ Phase 2 trials, only about 11 of them were people of color.

The diversity issues with MAPS’ trials reflect an ongoing problem in the clinical trial world, and in genomic and precision medicine, in general. The journal “Nature” reported that in 2014, nearly 86% of participants in clinical trials for the FDA were white.

Dr. Monnica Williams was the Lead Therapist and Principal Investigator of UConn’s team of MDMA-assisted psychotherapy researchers. Her team was intentionally diverse, to help bring new perspectives to the table. Psymposia previously reported that this study at UConn was shut down due to delays and the loss of their Schedule 1 license holders.

MAPS had previously said that their now-ended work with Williams at UConn was intended to remedy the lack of diversity for Phase 3 trials.

Now, Williams will pursue issues of diversity in psychedelic science through her own private practice, utilizing expanded access opportunities. Doblin admits that it could be harder to recruit diverse subjects through expanded access, because patients have to pay out of pocket for treatment.

Williams believes that a more diverse group of researchers and patients is a necessity.

“There are a lot of important questions, because not all drugs metabolize the same way in certain ethnic groups and types of therapy may not be as appropriate for some groups, as well,” Williams said.

Diverse participants — in race, nationality, and gender — could be ideal candidates for PTSD treatment with MDMA, as rates of trauma continue to increase in marginalized groups across the globe.

A recent report published in the Journal of Psychopharmacology, titled “The moderating effect of psychedelics on the prospective relationship between prescription opioid use and suicide risk among marginalized women,” backs up this assertion. It examined suicidal ideation and risky drug use in a group of nearly 900 sex workers in North America and found that the use of psychedelics “had a protective moderating effect on the relationship between prescription opioid use and suicide risk.”

The report concludes with an optimistic call to action for researchers in the psychedelic field.

“In the context of a severe public health crisis around prescription opioids and lack of addiction services tailored to marginalized women, this study supports calls for innovative, evidence-based and trauma-informed interventions, including further research on the potential benefits of psychedelics.”