mdma

more-bad-news-for-psychedelic-drug-company:-fda-expands-probe-after-rejection

More bad news for psychedelic drug company: FDA expands probe after rejection

health, lykos, maps, mdma, psychedelics, PTSD, Science / /

trippy trip up —

Psychedelic drug company Lykos already slashed staff and overhauled leadership.

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President of Multidisciplinary Association for Psychedelic Studies (MAPS) Rick Doblin speaks onstage during the 2023 Concordia Annual Summit at Sheraton New York on September 18, 2023, in New York City.

Enlarge / President of Multidisciplinary Association for Psychedelic Studies (MAPS) Rick Doblin speaks onstage during the 2023 Concordia Annual Summit at Sheraton New York on September 18, 2023, in New York City.

There’s more bad news for the company behind an experimental MDMA therapy for post-traumatic stress disorder, which the Food and Drug Administration roundly rejected earlier this month.

According to a report from The Wall Street Journal, the FDA is now expanding an investigation into clinical trials behind the experimental psychedelic therapy—even though the agency has already rejected it. Agency investigators reportedly interviewed four additional people last week, asking questions regarding whether the trials underreported side effects.

People involved in the trial have previously alleged, among other things, that ill effects, such as suicidal thoughts, went undocumented, and trial participants were discouraged from reporting them to bolster the chances of FDA approval. Overall, the MDMA trials faced crushing criticism amid the FDA’s review, with outside experts and agency advisors calling out allegations of sexual misconduct at one trial site, as well as flaws in overall trial designs, multiple sources of biases, and claims of that the company behind the therapy, Lykos, fostered a cult-like belief in psychedelics.

According to the Journal, the recent interviews were being conducted by the FDA’s Office of Regulatory Affairs, which oversees inspections, and a subdivision of that office called Biomedical Research Monitoring Program, which works to ensure the quality and integrity of data submitted to FDA. Notably, when the agency rejected MDMA, it advised Lykos to conduct a new trial.

While the FDA’s rejection and expanded investigation are bad enough for Lykos, the company announced this month that it’s laying off 75 percent of its staff and overhauling its leadership. The moves were in response to the FDA’s rejections, the company said. Additionally, a scientific journal retracted three of the company’s MDMA studies, citing “protocol violations amounting to unethical conduct” in its trials, echoing claims raised amid the FDA review.

Troubling roots

Underpinning the allegations and criticisms against Lykos is its roots in drug advocacy. Lykos is a commercial spinoff of the psychedelic advocacy nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS). For decades, MAPS has worked to legalize psychedelics and research their use as potential treatments, particularly mental health conditions, including PTSD, anxiety, and substance use disorders. MAPS was founded by Rick Doblin, a longtime psychedelic activist and advocate who openly believes the use of psychedelics will lead to world peace. Amid the leadership overhaul this month, Doblin left his position on Lykos’ board.

“After 38 plus years of work, I’m profoundly saddened by the FDA decision around this critically needed therapy, but am heartened that Lykos will still move forward continuing clinical research that addresses the FDA’s questions,” Doblin said in a statement. “I can speak more freely as a public advocate by resigning from the Lykos Board. The FDA delays make it more important than ever that I work at MAPS toward developing global legal access to MDMA and other psychedelics for public benefit through MAPS’ multidisciplinary research, education, and drug policy reform.”

Lykos did not immediately respond to Ars’ request for comment on the FDA’s investigation. In a response to the Journal, a company spokesperson said that “Lykos is committed to engaging with the FDA and addressing any questions it raises.” The spokesperson also noted that the company is planning to meet with the FDA about the rejection, which it is appealing.

But, trial participants and outsiders have levied heavy criticism against the company that will likely be hard to move beyond.

“The prospect of a therapy cult guiding a suggestibility-enhancing drug through clinical trials highlights unique risks that have never been publicly discussed,” Neşe Devenot, a Johns Hopkins University senior lecturer in the university’s writing program who focuses on the issue of drugs in society, said in public comments prior to the FDA rejection. “The trials should be scrutinized as if Scientology or NXIVM had submitted a new drug application to the FDA.”

Those public comments appeared in a damning report from Institute for Clinical and Economic Review, which concluded that there was insufficient evidence to back MDMA-based therapy. According to the Journal report, Devenot was among the people interviewed by FDA investigators recently.

Lykos’ saga has been a blow to the psychedelic community in general and to many patients, particularly veterans, who have reported benefits from using MDMA to treat PTSD, a condition in desperate need of effective treatments.

Amid Lykos’ troubles, the company has brought in David Hough as senior medical advisor to oversee clinical and regulatory work. Hough is a former vice president at Johnson & Johnson, where he notably helped develop Spravato—esketamine—a compound related to ketamine that was approved for use against treatment-resistant depression in 2019.

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FDA’s review of MDMA for PTSD highlights study bias and safety concerns

bias, clinical trial, fda, health, mdma, PTSD, Science / /

Complicated —

FDA advisors will meet June 4 to discuss and vote on the therapy’s effectiveness.

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MDMA is now in the FDA's hands.

Enlarge / MDMA is now in the FDA’s hands.

The safety and efficacy data on the use of MDMA (aka ecstasy) for post-traumatic stress disorder therapy is “challenging to interpret,” the Food and Drug Administration said in a briefing document posted Friday. The agency noted significant flaws in the design of the underlying clinical trials as well as safety concerns for the drug, particularly cardiovascular harms.

On Tuesday, June 4, the FDA will convene an advisory committee that will review the evidence and vote on MDMA’s efficacy and whether its benefits outweigh its risks. The FDA does not have to follow the committee’s recommendations, but it often does. If the FDA subsequently approves MDMA as part of treatment for PTSD, it would mark a significant shift in the federal government’s stance on MDMA, as well as psychedelics, generally. Currently, the US Drug Enforcement Administration considers MDMA a Schedule I drug, defined as one with “no currently accepted medical use and a high potential for abuse.” It would also offer a new treatment option for patients with PTSD, a disabling psychiatric condition with few treatment options currently.

As Ars has reported previously, the submission of MDMA for approval is based on two clinical trials. The first trial, published in Nature Medicine in 2021, involved 90 participants with moderate PTSD and found that MDMA-assisted psychotherapy significantly improved Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores compared with participants who were given psychotherapy along with a placebo. In the second study, published in September in Nature Medicine, the finding held up among 104 participants with moderate or severe PTSD (73 percent had severe PTSD).

In the briefing documents released Friday, the FDA highlighted that there was a high potential for bias to have crept into those results. Though the trials were designed to be double-blind (meaning that therapists and trial participants were not told who received MDMA), the FDA noted that MDMA “produces profound alterations in mood, sensation, suggestibility, and cognition.” Blinding is “nearly impossible,” the FDA wrote.  And indeed, approximately 90 percent of those assigned to take MDMA and 75 percent of those assigned to a placebo were able to accurately guess their treatment assignment, the FDA notes. As such, it is “reasonable to assume” that bias and “expectation bias” affected the results of the trials, the FDA concluded.

The agency also noted concerns that MDMA caused “significant increases in blood pressure and pulse,” which could trigger cardiac events, such as heart attacks. However, the trial data was limited for assessing the risks of these adverse events.

The FDA also dinged the studies for not including data on whether participants experienced effects such as “euphoria” after taking MDMA—an anticipated effect that could indicate the drug’s potential for abuse.

In all, the FDA’s review presented a complicated picture of MDMA’s risk-benefit assessment, one that should make for an interesting discussion Tuesday. The FDA’s criticisms follows an even more critical report released earlier this month by the Institute for Clinical and Economic Review (ICER), which identified “substantial concerns about the validity of the results” from the clinical trials.

Like the FDA, ICER found the trials to be “essentially unblinded.” However, ICER went further, having conducted a number of interviews with trial participants and others involved, finding that the trials largely pulled from an existing community of psychedelic advocates and supporters, introducing significant bias. “Concerns have been raised by some that therapists encouraged favorable reports by patients and discouraged negative reports by patients including discouraging reports of substantial harms, potentially biasing the recording of benefits and harms,” the report said. MDMA is known to induce confusion, depression, and paranoia in some. One participant reported feeling “relentlessly suicidal” after the trial, as a result of participating in it, but that result was not reflected in the trial’s reported results.

Various people told ICER that the community involved in the trials regarded psychedelics “more like a religious movement than like pharmaceutical products.” Some participants felt as though “they could be shunned if they reported bad outcomes or that it could lead to future patients being denied the benefits of MDMA-AP.”

In all, ICER concluded that the evidence available to assess for MDMA treatment is “insufficient.”

Editor’s Note: This story was corrected to report that the participant’s suicidal thoughts occurred after the trial, as a result of participation, not during the trial.

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MDMA—aka ecstasy—submitted to FDA as part of PTSD therapy

fda, health, maps, mdma, psychedelics, PTSD, Science, therapy / /

Groovy —

If FDA approved, it would require the DEA to reclassify MDMA.

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Girl with an ecstasy tablet on her tongue.

Enlarge / Girl with an ecstasy tablet on her tongue.

A corporation dedicated to studying the benefits of psychedelic drugs filed an application with the Food and Drug Administration this week for approval to use MDMA—aka ecstasy or molly—in combination with talk therapy to treat post-traumatic stress disorder.

If approved, it would be the first-of-its-kind combination treatment—a psychedelic-assisted therapy. An approval would also require the Drug Enforcement Administration to reclassify MDMA, which is currently in the DEA’s most restricted category, Schedule I, which is defined as drugs “with no currently accepted medical use and a high potential for abuse.” The category also includes LSD, heroin, and marijuana.

The public benefit corporation (PBC) that filed the FDA application was created by MAPS, The Multidisciplinary Association for Psychedelic Studies, which has been supporting this type of work since 1986. The application is based on positive data from two randomized, double-blind, placebo-controlled Phase III studies, which were funded and organized by MAPS and MAPS PBC.

The first study, published in Nature Medicine in 2021, involved a total of 90 participants with moderate PTSD. It found that MDMA-assisted talk therapy (aka psychotherapy) significantly improved Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores compared with participants who were given talk therapy with a placebo. In the second study, published in September in Nature Medicine, the finding held up among 104 participants with moderate or severe PTSD (73 percent had severe PTSD).

In both trials, participants took 80 to 180 mg doses of MDMA or a placebo at the start of three eight-hour sessions, which were spaced around a month apart. Between those experimental treatment sessions, participants also had three 90-minute sessions for participants to process the experimental experience.

MDMA—3,4-methylenedioxymethamphetamine—affects neurotransmitters in the brain, increasing the activity of serotonin, dopamine, and norepinephrine, to be specific. This leads people who take the drug to experience euphoria, hallucinations, sharpened sensory perception, and sociability, but it can also induce confusion, depression, and paranoia. Its use in psychotherapy has been explored for decades.

In a statement this week, MAPS PBC CEO Amy Emerson celebrated the FDA submission. “The filing of our [new drug application] is the culmination of more than 30 years of clinical research, advocacy, collaboration, and dedication to bring a potential new option to adults living with PTSD, a patient group that has experienced little innovation in decades,” she said.

MAPS founder and President Rick Doblin also celebrated the submission this week, saying in a statement: “When I started MAPS in 1986, the FDA was still blocking all research with psychedelics. … By breaking that barrier, we have opened doors for others to conduct their own promising research into psychedelic-assisted therapies with psilocybin, ayahuasca, ketamine, and more. The novel approaches undertaken in psychedelic-assisted therapy research have led to fundamental shifts in our understanding of how these devastating mental health conditions can be treated.”

So far, the MDMA-assisted therapy has drawn criticism for its expected inaccessibility. The treatment outlined in the two MDMA trials involves lengthy—and likely pricey—therapy sessions with highly trained therapists. The Washington Post published an estimated price of between $13,000 to $15,000 per treatment round, and it’s unclear for now whether it would be covered by health insurance if approved by the FDA. “Most people in the world won’t be able to afford these clinics,” Allen Frances, a Duke University professor emeritus of psychiatry, told the Post.

Now that the NDA is submitted, the FDA has 60 days to determine whether it will be accepted for review and whether it will be a priority or standard review (six months or ten months, respectively), MAPS PBS noted. MAPS is seeking a priority review. In 2017, the FDA granted MDMA “Breakthrough Therapy,” designed to help hasten the development and review of drugs for serious conditions when evidence indicates they may substantially improve upon current therapies.

The only psychedelic with FDA approval to date is esketamine, a variation of ketamine, which was approved in 2019 to treat treatment-resistant depression.

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