MDMA rejection poses questions for psychedelic drug trials

The US Food and Drug Administration (FDA) has rejected MDMA as a psychiatric treatment for post-traumatic stress disorder (PTSD). US based Lykos Therapeutics had hoped to get the active ingredient in the club drug ecstasy approved for use in combination with psychotherapy.

Instead, on 9 August, the FDA asked for a further phase 3 clinical trial to collect more data on both safety and efficacy. The decision follows an overwhelming majority of the agency’s advisory committee agreeing on 4 June that Lykos’ application was lacking on both fronts. In a statement, Amy Emerson, Lykos’ chief executive, said that ‘conducting another phase 3 study would take several years’.

Then, on 10 August, editors at the journal Psychopharmacology retracted three papers from researchers affiliated to Lykos’ predecessor, MAPS Public Benefit Corporation (MAPS-PBC). Two of the papers involved analysis of six clinical trials included in the FDA submission. The editors’ notices cited ‘protocol violations amounting to unethical conduct’. On 15 August, Lykos announced that it will cut about 75% of its staff and that Rick Doblin, who pioneered the therapy, is stepping down from the board to enable him to advocate more freely for psychedelic therapies.

Though some dispute MDMA’s psychedelic status because it rarely causes hallucinations, it has played a significant role in recently resurging medical interest in such drugs. Therefore, other researchers exploring related treatments for conditions such as depression and addiction stand to learn much from Lykos’ crisis.

Michael Abrams, a senior researcher at nonprofit consumer advocacy organisation Public Citizen, attended the June FDA committee. Public Citizen strongly asserted that the data was far from good enough for consideration. ‘We’re glad they rejected the therapy,’ Abrams tells Chemistry World. ‘But there’s some question about why we got to this point, given how weak the trial was and then ethical concerns that emerged later.’

Vulnerable to abuse

The decision represents a striking change in MDMA’s trajectory. Back in 2017, the FDA had granted the drug an expedited review process. That was spurred by promising early findings that suggested MDMA, in combination with psychotherapy, could offer relief for millions suffering from PTSD, including many military veterans.

Lykos applied for the right to market MDMA, which it refers to as midomafetamine, providing apparently strong data from two phase 3 trials showing reduced scores for PTSD symptoms. The company had hoped to only require one such trial. However, the FDA asked for a second, which included improved policies on misconduct after two therapists abused a patient.

The June panel had several concerns about the psychotherapy aspect of the trial, with the FDA stressing that it ‘does not regulate the practice of psychotherapy’. The 11-member panel ruled 9-2 that the evidence does not demonstrate the drug’s effectiveness, and 10-1 that its potential benefits do not outweigh the associated risks.

Abrams highlights the need for still stronger measures to protect patients from abuse during the multi-hour therapy sessions, which was discussed during ‘riveting testimony’ at the committee meeting. ‘This is a very intensive treatment, a vulnerable position, and then you add on top of it that you’re giving somebody a substance that is really very destabilising,’ Abrams says.

Other concerns raised included that the trial participants’ responses may have been biased by expecting a benefit when they received MDMA, whose effects were obvious. And if the participants experienced negative effects, some researchers conducting the trial may have discouraged them from reporting them. ‘People came out as very critical of Lykos, very concerned about their experiences during the treatment,’ says Abrams. ‘You should have safeguards in place and make darn sure that these kinds of abuses do not occur.’

An unnecessary combination?

However, it should be possible to develop related psychiatric drugs avoiding such psychotherapy entirely during trials, according to David Olson from the University of California, Davis in the US. ‘If a drug is safe and efficacious on its own, there is no reason that a doctor can’t prescribe it with psychotherapy, as the FDA does not regulate the practice of medicine,’ adds Olson. ‘As an example, ketamine is approved as a stand-alone treatment for depression, but many practitioners will combine its use with psychotherapy.’

There isn’t a reasonable regulatory framework in place yet for vetting and approving these combination treatments

Holly Swartz, University of Pittsburgh

Meanwhile, Holly Swartz from the University of Pittsburgh, US, points out that the FDA is actually taking its first steps into regulating some forms of psychotherapy. The agency’s Center for Devices and Radiological Health approved a prescription-only, app-based cognitive behavioural therapy programme from Otsuka Pharmaceuticals in May. However, drugs such as MDMA are assessed by the Center for Drug Evaluation and Research, and Swartz notes the two FDA centres’ approaches are very different. ‘My impression is they don’t really talk to each other,’ she adds.

As such, the MDMA situation reveals structural issues with how regulators think about psychotherapy, Swartz underlines. ‘These applications of psychedelics are really about opening people up to the therapy experience, so they go hand in hand. But there isn’t a reasonable regulatory framework in place yet, I think, for vetting and approving these combination treatments,’ she says. ‘There have been dismantling studies where you look at psychotherapy and pharmacotherapy in combination or individually. In many instances there are additive effects, so considering them as separate entities, regulating them separately, doesn’t make sense to me.’

She also adds that there are existing, effective, evidence-based psychotherapies for PTSD that sufferers can’t get access to, owing to bottlenecks in training therapists and disseminating treatments.