Ecstasy Drug Trials Missed Suicidal Thoughts Of Subjects

                                                             By Liz Essley Whyte

Participants in studies of the psychedelic, which is up for U.S. approval, said they felt pressure to report positive outcomes.

Studies being used to decide whether the U.S. should authorize an ecstasy-based drug for traumatized patients missed serious side effects and were marked by bias.

The Food and Drug Administration is expected within days to decide whether to approve the drug, known as MDMA, for treatment of post-traumatic stress disorder. Approval would be a milestone in decades of efforts to decriminalize the use of psychedelics.

Three people who were subjects in the studies said that their thoughts of suicide worsened during or after testing, but their downward slides weren’t captured in trial data and therefore not reflected in the final results.

The study subjects said they felt pressure to report positive outcomes, because that would lead to a history-making drug approval. They also said they could tell they had taken ecstasy during the studies, though gold-standard drug trials are supposed to mask whether a subject got the drug candidate or a placebo.

“I wanted the miracle cure,” said Sarah McNamee, one of the subjects. She said the therapists conducting the trial did, too. “My therapists made it really clear that they really really believed in this thing.”

Lykos Therapeutics, the company sponsoring the studies, recruited researchers conducting the testing from the ranks of therapists who had given ecstasy illicitly and advocated for the drug’s use, according to people familiar with the matter. Some researchers conducting the trials ran underground therapeutic ecstasy sessions on the side. MDMA is illegal to use outside of certain specific situations, mainly scientific research.

The company said any issues voiced by a small number of study subjects shouldn’t undermine the overall study results. Lykos said it planned the trials in collaboration with the FDA, and that boards of independent trial overseers approved the designs. The company said an independent committee of study experts monitored the ethics and safety of the trials.

Lykos also said it didn’t recruit therapists or patients from the ecstasy underground and wasn’t aware of any therapists who were giving ecstasy illegally while conducting the trials, which were evaluating whether a combination of Lykos’s drug and mental-health therapy safely treated PTSD.

“We really feel that they are sound,” said Lykos Chief Executive Amy Emerson. “The data is reliable.”

FDA staffers have questioned the quality of the study results. Experts advising the agency recommended against approval, saying more safety and effectiveness evidence was needed. The Institute for Clinical and Economic Review, a nonprofit that reviews drugs and their prices, said the evidence was incomplete.

The FDA told its advisers that it is looking into allegations of study misconduct and missing side effects. It said that it can’t comment on investigations until they are final, but its findings will be incorporated into its decision on the Lykos treatment.

Problems with the trials mean the FDA might not be able to assess whether the treatment is safe and effective for everyone, or just some people, said experts advising the agency and bioethicists who spoke about its findings.

“We have to be able to rely on the data. That’s all we have,” said Holly Fernandez Lynch, an associate professor of medical ethics at the University of Pennsylvania. “We can’t approve drugs on the basis that people think they work.”

Lykos’s study of its drug-therapy combination has been troubled. One subject of an early trial alleged in a lawsuit and told FDA advisers that she was sexually assaulted and abused at the hands of married therapists overseeing her participation in the trial. Videos from her clinical trial sessions showed both her male and female therapists holding her closely while lying together on a bed. The parties agreed to dismiss the lawsuit, but the terms weren’t disclosed.

Lykos has said that what happened was malpractice and that it cut ties with the therapists.

Veterans urge approval

MDMA, or midomafetamine, is a synthetic drug that acts as both a psychedelic and a stimulant, affecting hormones in the brain. For decades, it has been used illegally, at parties and raves.

Supporters have long theorized the drug could be a helpful treatment for mental-health conditions such as post-traumatic stress disorder. They formed a movement pushing for legalization of psychedelics and have conducted underground therapy sessions or retreats with the drug.

An estimated 13 million Americans, including veterans and victims of sexual assault, suffer from PTSD. The few available medicines approved for treatment don’t work in many patients. Groups supporting veterans, who face high levels of suicide, have pressed the FDA to approve the MDMA drug.

To assess whether its drug-therapy combination worked safely, Lykos sponsored a number of trials. Among them were two final-stage studies, enrolling nearly 200 subjects with either severe or moderate PTSD, that the FDA agreed to review to decide whether to approve the treatment.

The studies evaluated subjects for 18 weeks of treatment with drugs—or a placebo—and psychotherapy. Some subjects completed a separate, follow-up study months afterward.

During the 18-week trials, Lykos said, most of the study subjects who received MDMA therapy improved significantly on an assessment of their PTSD symptoms. Some no longer qualified for their original diagnosis. The company said side effects were mostly mild to moderate, and transient.

In the long-term study, the positive effects from the initial MDMA treatments endured, for some patients as long as two years later, the company said.

“It was incredibly healing,” said Wade Kodrin, an Army veteran who was in one of the studies. He said the drug therapy helped far more than did other therapies and treatments he had tried for his PTSD for more than a decade.

Suicidal thoughts

Other patients said the treatments made them feel worse overall. McNamee, from Montreal, said the drug therapy made her feel as if she was “cracked open” and resurfaced memories from various traumatic events in her life. For about a year after, she said, she spent her days trying not to attempt suicide.

To measure how McNamee and other subjects fared during testing, researchers asked a series of standardized questions. The scores from McNamee’s interviews, indicated that McNamee got better.

That was partly because the scores measured, under the trial’s design, McNamee’s symptoms related to one traumatic experience only. Those symptoms, including nightmares related to the trauma, improved. Yet she said she spiraled downward while thinking of other traumatic events.

Pressure to report positive results also played a role, McNamee said. Therapists conducting the studies told her she was helping make history.

“It made me feel like I belonged to something bigger than me, and it also made me feel like I had a serious responsibility to make sure that other people could get access,” she said.

Two other study subjects, who declined to be named because talking about their MDMA use in the trials could hurt their employment or relationships, said they had suicidal thoughts after getting the drug therapy as part of the trials. They didn’t fully report that to researchers, they said, because they felt pressure to support the therapy’s approval.

They said they thought their negative symptoms could impede the drug’s progress toward legalization, which they felt was important.

Both of the subjects said their mental health worsened after the trial ended and researchers were no longer collecting data.

One of the subjects said she didn’t join the long-term study because she felt unable to function, was depressed and had suicidal thoughts.

The other subject, who participated in the long-term study, said she didn’t report that she had become more suicidal after the initial trial had ended. The study questions, she said, focused on the previous several months during which she felt better, and not on the full amount of time since the trial when she was at her lowest. Lykos said it asked about the worst suicidal points.

Bioethicists said studies should make sure all serious side effects are reported to determine whether a drug candidate is safe.

Pressuring study subjects to report positive results is “a serious problem to me. That’s not how you’re supposed to do science,” said Jonathan Kimmelman, a bioethicist at McGill University.

Lykos said it monitored suicidal thoughts and actions regularly throughout the trials to check on subjects’ safety. It said specially trained professionals, who looked out for subjects playing down or overplaying symptoms, conducted the interviews evaluating the effectiveness of the drug therapy.

Lykos also said it reported any significant increases in suicidality to the FDA and that most of the patients had a history of suicidal thoughts.

“An important thing to remember is that this is a very sick population of people that we’re taking care of,” said Dr. Alia Lilienstein, senior medical director for Lykos.

Studies of people taking experimental medicines are highly regulated to minimize bias and accurately assess whether a drug works safely. To reduce the risk that either researchers or subjects selectively report results, the FDA usually requires the random assignment of the study drug or placebo.

Most subjects could easily tell, given the drug’s hallucinogenic effects, whether or not they had received a placebo, according to a Lykos survey of study subjects.

The awareness could have affected the study’s findings, FDA staffers said in their review of the results: It “can introduce bias in clinical studies.”

Therapists who believe

The trials were run by therapists who spoke about the benefits of the MDMA drug, according to people familiar with the studies.

“You want to make sure that the therapists are very, very clear that they should not be implying to people that it’s globally important what the results of the trial are and encouraging people to have favorable outcomes,” said Dr. David Rind, ICER’s chief medical officer.

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