Psychedelic Therapy Sees Challenges Despite Promising Results

6 min read

June 5, 2024 – When Victoria Tennant, 31, woke up the day after her first psychedelic treatment, she felt like someone had taken her “brain out, put it in a bowl of ice, and then put it back” in her head. She just felt lighter, the Los Angeles-based neuroscience PhD candidate said. 

She’s receiving weekly nasal esketamine – a cousin to the better-known anesthesia drug ketamine – for treatment-resistant depression. The FDA approved the medication – packaged and sold by Janssen Pharmaceuticals under the brand name Spravato – in the spring of 2019. It’s the first drug of its class of psychedelics to hit the mainstream market, carving out a path for others, namely MDMA and psilocybin, to potentially follow in its footsteps.

Tennant has been on antidepressants for 6 years, partnered with regular therapy appointments. Despite hitting what felt like a mental roadblock in her recovery, she never thought ketamine treatment would be an option for her until she found out that, under her insurance, she qualified for Spravato at just $10 a session. She started her first round of treatment 6 weeks ago and has since felt a significant change in her daily depression symptoms.

“I’ve felt more of an ease when it comes to just getting up in the morning,” she said. “Instead of it being so hard and taking so much mental energy, I’m able to get up and get stuff done.”    

But now, as these types of psychedelics are gaining more mainstream approval, some forward-looking organizations want to make their use allowed by the government and health insurance companies. But obstacles remain. 

The data on esketamine has shown that most patients saw improvements in their depression symptoms in both the short and long term, and were less likely to have a relapse when the drug was taken with their prescribed antidepressant of choice. 

Ketamine itself is not approved for depression treatment, although it is often prescribed off-label and given intravenously. Esketamine, which differs slightly from ketamine, is FDA-approved as a nasal spray for adults with treatment-resistant depression or major depressive disorder with suicidal thoughts or actions, in combination with an oral antidepressant.

Like ketamine, MDMA – commonly known as ecstasy or molly – has the reputation of being a party drug. It falls under the same umbrella of psychiatric psychedelics, even though it comes from amphetamine, a stimulant, as opposed to ketamine, which is a dissociative anesthetic. 

Studies of MDMA use for the treatment of posttraumatic stress disorder (PTSD) have been in the works for years, spearheaded by Lykos Therapeutics (formerly called MAPS Public Benefit Corporation). 

Dr. Bronner’s, the popular soap company known for its organic products, has gone so far as to donate $5 million to Lykos in support of its research, and has been working with Enthea, a nonprofit startup, to get psychedelic-assisted therapy covered by their employee health benefits plan. 

It Atlanta, City Council Member Liliana Bakhtiari has filed legislation that would require the city's human resources department to study the pros and cons of ketamine and psilocybin for city employees to treat mental health issues and to find out if the employee health plan could cover the treatments

Lykos’s phase III clinical trial, the results of which were published in September 2023, showed promising results. After 3 months of MDMA sessions and talk therapy appointments with Lykos-trained personnel, 71% of patients no longer met PTSD criteria, in comparison to the 48% from the placebo group. 

But that alone wasn’t enough to get the therapy FDA-approved. The FDA's Psychopharmacologic Drugs Advisory Committee shot it down Tuesday by a vote of  9-2 on the drug’s efficacy and 10-1 on whether the benefits outweigh the risks, recommending that the FDA not go through with an approval. 

So why does MDMA’s path look so different from ketamine’s? It might all boil down to the foundational weaknesses of Lykos’s trials. 

The pool of people in the study is already smaller than those of most phase III trials, with only 104 patients, and 94% of those who were not in the placebo group and received MDMA were able to correctly identify which group they had been in, which means the trial wasn’t blinded. 

This was a major concern for David Rind, MD, a primary care doctor and chief medical officer of the Institute for Clinical and Economic Review, which published a report in March detailing their concerns about the MDMA study. 

“We have seen over and over again in medicine that when we don't do blinded trials, we make mistakes,” he said. “People’s opinions about the therapy they get influences results.” 

In addition to the lack of blinding, several allegations of misconduct came to light – detailed in episodes of New York Magazine’s Cover Story podcast and investigated independently by the institute – from some people in the study who said they were actively harmed over the course of the trial, experienced inappropriate behavior from therapists, or felt pressure to report overly positive outcomes so as not to hinder MDMA’s potential future in treating PTSD. But it remains unclear how pervasive these issues were. 

“It's not that nobody gets benefits, or that everybody gets harmed, but it's very important how often people get benefits and how often people get harmed – and that's really hard to tell right now,” said Rind. 

What makes MDMA distinct, says proponents and naysayers alike, is its ability to make people feel more emotionally open and socially connected. Yet, it’s for this reason that MDMA therapy for PTSD would be so much harder for health care providers to prescribe and for patients to access. 

“MDMA creates such positive feelings of trust and connection that there have been a few incidents of inappropriate sexual contact between participants in [a previous] study and the people who are providing support in the study,” explained John Krystal, MD, psychiatry chief at Yale-New Haven Hospital. “It's very rare, but it's pretty extraordinary.”

It’s hard to draw parallels here, said Krystal, who has particular expertise in ketamine-assisted therapy, because esketamine is a sedative, historically used as an anesthetic in medical environments; so patients in a ketamine infusion session aren’t normally stimulated in the same way as they are with MDMA. The staffing requirements would make the cost of running MDMA treatment centers much steeper than anything we’ve seen before in the world of psychedelic therapy, and may, in turn, make the price of admission even higher for prospective patients. 

But Lykos is still forging ahead with research on MDMA and PTSD, despite of the recent setback. The company is sponsoring a new study led by Brown University researchers Christy Capone, PhD, and Erica Eaton, PhD, focusing on MDMA-assisted therapy for PTSD and substance use disorder treatment among veterans. 

Capone and Eaton can see how the resource-intensiveness of MDMA-assisted therapy might be daunting, but they have a different perspective. 

“While it might be more resources upfront, we’re seeing effects up to 2 years of people feeling better and not needing to come into treatment as often,” said Eaton. “Christy and I both regularly see patients for years and don’t see that kind of improvement. So, while it’s resource-heavy upfront, it may actually be more bang for our buck in the long run.”