A therapy room at Field Trip, a psychedelic therapy clinic in Toronto, Canada. (Photo by Cole ... [+]
Today, MDMA is probably best known as a “party drug,” more likely to be passed around on a sticky dance floor under UV lights than in the psychiatrist's office.
But after decades of prohibition scientists have begun to rediscover its potential—along with a number of other psychedelic drugs—in the treatment of complex trauma-related mental health conditions.
The U.S Food and Drug Administration is currently reviewing a new drug application (NDA) which would see MDMA (midomafetamine capsules) capsules delivered alongside psychotherapy for the treatment of PTSD.
It would be the first psychedelic-assisted therapy to be given the green light in the U.S and would require the Drug Enforcement Administration to reschedule MDMA under the Controlled Substances Act, in order for it to be legally prescribed as pharmaceutical.
A decision from the FDA is expected by August 2024, with the application having been granted priority review for drugs that, if approved, would represent “significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.”
MDMA-Assisted Therapy In Context
The hype around psychedelics has been gathering momentum, spurred on by a gradual shift in attitudes to global drug policy, a need for new treatment options to tackle rising rates of mental illness and ultimately, financial investment in commercial development.
In July 2023, Australia authorized the prescription of MDMA and psilocybin for use in psychedelic-assisted psychotherapy to treat specific mental health conditions, making it legal for authorized psychiatrists to prescribe to those experiencing PTSD and treatment-resistant depression.
But as with many of these substances, the use of MDMA as a therapeutic is not a new phenomenon. As far back as the 1970s, it was used by mental health professionals in conjunction with talking therapy to enhance patients' access, processing, and communication of difficult emotions and experiences. After the DEA made MDMA a Schedule I drug under the Controlled Substances Act in 1985, it was no longer legal for recreational or medical use and conducting research in this area became significantly harder.
In a press release in December 2023, Rick Doblin PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS), the organization which has been at the forefront of research in this field, said: “When I started MAPS in 1986, the FDA was still blocking all research with psychedelics. MAPS had to try, though we might never succeed, to gather sufficient data about the safety and efficacy of MDMA-assisted therapy to seek approval for prescription use.
“As it has turned out, it took 37-and-a-half- years to gather the necessary data to seek approval! All the effort and time have been totally worth it for the progress that we have seen in our research and the millions of people we hope to help through the public-benefit pharmaceutical model if the FDA does approve the treatment.”
The Science Behind MDMA For PTSD
Despite the restrictions on research, some studies have been published which support its use alongside psychotherapy due to its effect on the brain's fear response, enabling people to access and process more painful memories without becoming overwhelmed.
In its FDA application, Lykos Therapeutics (formerly MAPS Public Benefit Corporation), included results from a number of studies including two randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of MDMA in combination with psychological intervention in participants diagnosed with severe or moderate to severe PTSD.
In 2021, a Phase 3 trial led by Lykos Therapeutics, reportedly found that 67% of participants no longer qualified for a PTSD diagnosis after receiving three MDMA-assisted therapy sessions.
A second Phase 3 trial, confirming these results, was published in the journal Nature Medicine in September 2023. Although evaluations were only carried out up to two months after treatment and long-term data is needed to “assess the risk of MDMA abuse or misuse after study participation,” the researchers say.
They also note a number of limitations that could impact the roll-out of MDMA-assisted therapy in clinical care, including the need for future studies to examine the “complex relationship” between the treatment and a history of SSRI use in a larger sample size.
Comparison studies are also needed to determine whether MDMA-assisted therapy provides “greater value” than current first-line treatments, including cognitive behavioral therapy and prolonged exposure therapy.
Dr James Rucker, a consultant psychiatrist and senior clinical lecturer in mood disorders and psychopharmacology at King’s College London, has been working on similar studies in the U.K.
“The action of the drug allows people to re-experience the trauma that they've been through without getting overwhelmed and resorting to avoidance behaviors that compound the original problem,” he says in a phone interview.
When MDMA interacts with the brain it leads to the release of neurotransmitters such as serotonin, dopamine and oxytocin, which in part help to suppress the amygdala—the part of the brain responsible for what is known as the “fight or flight” response—as well as inducing feelings of warmth, empathy and connection to others, Dr. Rucker explains.
The sessions take place in what he describes as a “comfortable living room within the safety of a mental health facility” to create the necessary setting to instill a sense of safety and comfort, with the reassurance of clinical staff on hand should anything go awry.
“That sense of warmth, trust and openness, as well as the quietening down of the bit of the brain that is otherwise triggered all the time in PTSD, and within the safe, supportive context of ongoing psychotherapy, creates a window of opportunity for people who have otherwise been stuck to start to make progress,” he says.
“It's a catalyst for positive change.”
Promise For Those With PTSD
It is estimated that 50-70% of people will experience a significant trauma at some point in their life and of those, 20% will go on to develop PTSD.
According to the World Health Organization (WHO), approximately 3.6% of the global population has experienced PTSD in any given year, equating to 250 million people affected by the condition.
In Ukraine, which hosted an international conference on psychedelic therapy in the treatment of post-traumatic syndromes in 2023, the number of people experiencing PTSD is thought to have risen significantly since Russia invaded in February 2022.
Ukrainian MP, Dmytro Gurin, recently called for MDMA-assisted therapy to be considered as a frontline treatment for PTSD due to the large number of patients mental health services are currently providing support for.
“It is important for the patient community that a spectrum of effective methods of combating the consequences of war is available in Ukraine,” Iryna Rachynska, advisor on Communities and Partnerships Development for the campaign group Patients of Ukraine, said in an email.
“There is no universal way to overcome PTSD; now deputies, Ukrainian doctors, and scientists are exploring different ways to help our people.”
According to Dr. Ksenia Voznitsina, at the Center for Psychological Health and Rehabilitation of Veterans (Lisova Polyana), psychedelic-assisted therapy is not the only solution for people with PTSD, but the “prospects of the method are quite powerful,” Rachynska says.
And Dr. Rucker agrees.
“In my opinion, it’s quite an empowering form of therapy,” he says.
“It teaches people a form of self-empathy and self-compassion that they can take away and apply in their everyday lives.”
He adds: “Of course, psychotherapy can do that as well, but drug-assisted psychotherapy seems to get to the places that talk and behavior-based psychotherapy alone struggle to, or take a very long time to. A drug intervention that speeds that process up could make a lot of sense, if you can deliver it safely.”
The Challenge For Regulators
But psychoactive drugs present a dilemma for regulators.
Randomized control trials—widely viewed as the gold standard in scientific evidence and crucial for the authorization of any new drug—are designed on the basis that participants don’t know whether they have been given the drug or a placebo (or “control”).
In June 2023, the FDA issued draft guidance for clinical trials on psychedelic drugs, aiming to help researchers design studies that will yield more reliable results.
“For psychoactive drugs, when people inevitably know whether or not they're on the placebo or the drug you've got a problem. Are you seeing a direct drug effect, or what we might call a ‘drug-induced expectancy effect,’” Dr. Rucker explains.
“It is most likely to be both, but it can be very hard to tell how much each effect is contributing to the outcome.
“From that perspective, though, the trials more represent what we do in the real world. In the real world everyone knows what treatment they're getting. Patients and doctors make their choice about treatments, and we always try to combine drugs with forms of psychological support that aim to enhance the effects.”
If the FDA decides to approve the application later this year, this will have a major knock-on effect among regulators around the world, not only for MDMA-assisted therapy but potentially other psychedelic-based treatments too.
“Inevitably, regulators would need to take a certain ‘leap of faith’ in licensing MDMA therapy. Time will tell if they do,” says Dr. Rucker.
“My instinct is that it will get across the line, and at that point a whole new question opens up about how to deliver it safely, in a properly regulated fashion.
“Drugs like MDMA put people into a psychologically vulnerable state. For the sake of everyone involved, safeguards and regulations need to be in place that ensure that the therapy is of good quality, and that proper boundaries are maintained.”
And “taking the shackles off” without the right regulations and safeguards in place, could result in what he describes as a “race to the bottom” among more commercially opportunistic psychedelic therapy clinics.
“I have been in psychiatry for 20 years now and the potential opportunity here is exciting,” he adds.
“There's a lot of hype around it and I think you have to be mindful about that, but there is genuine optimism.
“However, from a clinical perspective, we shouldn't let it spin out of control, and it is my firm belief that these drugs need to be properly regulated.”
Questions That Remain Unanswered
MDMA remains illegal under federal law, and medical bodies such as the American Psychiatric Association have not yet endorsed the use of psychedelics except in clinical trials due to a lack of evidence.
In 2022, a study published in JAMA Psychiatry, by Dr. Joshua Siegel and colleagues at Washington University pointed out that while legislative reform for psychedelic drugs is moving forward several issues have not been addressed in the scientific evidence.
Dr. Siegel and colleagues state: “Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.”
April 2. 2024: This article was updated to clarify that Lykos Therapeutics led the FDA submission and Phase 3 clinical trial.
