If you have 8 hours to spare, the FDA Advisory Committee’s meeting on MDMA is available on Youtube. If you’d rather not subject yourself to that level of torment, I’m here to offer a quiet perspective on the topic.

Background

Earlier this month, the FDA Advisory Committee rejected the new drug application for MDMA-assisted psychotherapy, submitted by Lykos Therapeutics (formerly known as MAPS). This news was a major setback in the psychedelic industry, as many expected the drug application to be approved by the committee.

Prior to the FDA committee meeting, the Institute for Clinical and Economic Review (ICER), a research nonprofit, published a detailed report and held a separate meeting on MDMA. Both ICER and the FDA cited concerns about how the trials were conducted; among the concerns, there was particular emphasis on the following themes:

• Therapy - Several concerns, including sexual assault, were centered around the therapy component. There were discussions on boundaries, how many therapists should be in the room etc.

  • Sexual Assault - A research participant was sexually assaulted by her therapist during an MDMA phase 2 trial conducted by MAPS. The assault was recorded on camera, and the FDA noted an investigation.

  • The problem is - the FDA doesn’t regulate therapy. Because the drug is to be used in combination with therapy, there is a general lack of regulatory continuity.

    • The FDA noted that there are already regulatory agencies for licensed therapists.

• Blinding - In placebo controlled trials, blinding is the process of concealing to the patient whether they’ve received the placebo or the active drug. However, in psychedelic trials it’s very difficult to do because people generally know when they are under the influence of a consciousness altering drug like MDMA or Psilocybin.

  • MDMA isn’t a classical psychedelic like psilocybin, LSD or DMT, but the perceptual effects present similar challenges to clinical trials for mind altering drugs.

  • Because the patient likely knows that they’ve take the drug, there is a concern about expectancy bias influencing the efficacy results.

  • In the case of the patient, especially if they benefit from the drug, there is a case to be made for why it matters.

  • In the case of the pharmaceutical company, there is a case to be made for making sure the drug is better than placebo to charge money to patients.

Just the Tip

Women’s Health

During the FDA livestream, Dr. Jess G. Fiedorowicz, Senior Research Chair, University of Ottawa asked Lykos: “Was there any evaluation for sex or gender differences in the efficacy or side effects?”

Lykos Response: “We do have an analysis on whether there was an effect of sex in the efficacy results. What we saw was that males and females still had results that favored MDMA, and as a reminder the ratio was 2 to 1 which is what we see in the broader patient population. In terms of adverse events, I’ll have to check with my team to see if we have a slide that sorts that and get back to you after the break.”

It’s unclear from the live broadcast if the question about adverse events was ever answered by Lykos during the meeting, or after the meeting. Lykos did mention that PTSD effects twice as many females as males, and the 2 to 1 ratio was reflected in the trials.

Advocacy

In response to ICER’s request for public comment on MDMA, the Dysphoric Project submitted an advocacy letter outlining issues with the MAPS study protocol as it relates to women. In the letter, we cited findings from a paper that was referenced by MAPS in the study protocol document:

“The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the [serotonin] 5-HT-releasing effects of MDMA.” 

110. Liechti, M.E., A. Gamma, and F.X. Vollenweider, Gender differences in the subjective effects of MDMA. Psychopharmacology (Berl), 2001. 154(2): p. 161-8.

Despite this paper being referenced by MAPS, there is no evidence that it was considered in the trials, and data on adverse events was not provided by sex. Based on the clinical data provided by Lykos, there is no way to determine if women are at a higher risk for adverse events than men. Because PTSD affects twice as many women as it does men, we really do need to understand this before it’s rolled out in a medical setting.

Open Letter

In response to the Lykos drug application, the Dysphoric Project also published an Open Letter to the FDA in partnership with Hystelica, and submitted public comments to the FDA Advisory Committee. In those documents, we cited concerns about informed consent, and the lack of female-specific variables like menstrual cycle phase in the trial design - despite the large body of evidence showing that the serotonergic system interacts with the menstrual cycle.

Informed Consent

Informed consent for women of reproductive age is an issue with psychedelic research. There is almost nothing known about psychedelics and the female reproductive system, despite the known fluctuations in serotonergic activity across the cycle. It’s also unclear if menstruation, or feminine hygiene, is being considered at all, and how that may have play out during the sessions.

In a Draft Stakeholder Report, we’ve outlined the following issues with informed consent:

• Contraceptives are often encouraged or mandated in trials to reduce the risk of pregnancy. However, there is no known data available on the pharmacokinetics of psychedelics and the effect of exogenous hormonal therapy, or the effect of the drug on the pharmacokinetics of oral contraceptives. These data requirements are outlined in the FDA’s Evaluation of Gender Differences in Clinical Investigations.

• Introducing hormonal components into psychedelic study design, prior to understanding the potential interaction between psychedelics and hormonal contraceptives, or the stages of the menstrual cycle, may lead to unreproducible results for female subjects, and may increase the risk of adverse drug reactions.

• Oral contraceptives, in particular, carry their own risks related to cardiovascular events, which calls into question whether this drug combination should be considered a compounding risk factor when taken alongside MDMA or classical psychedelics.

• Very little is known about the psychedelic experience and menstruation, which could lead to unknown discomforts and risks of dosing during this time. It’s unclear if clinical investors are taking into account feminine hygiene such as changing tampons, pads, or menstrual cups while under the influence of psychedelics.

• Female specific mental health conditions related to the menstrual cycle such as premenstrual dysphoric disorder, premenstrual syndrome and premenstrual exacerbation of underlying conditions, should be considered when scheduling the timing of dose for females of reproductive age, as it is unknown whether or not psychedelic drugs may exacerbate these conditions.

Recruiting Women for Research

It’s unfortunate that Lykos failed to consider female-specific risks, especially considering that their largest patient demographic is women. It’s extra salt in the wound that a woman was sexually assaulted during a trial that was never designed to collect female data points in the first place.

It’s often cited in the research community that it is difficult to recruit women for clinical trials. Some have speculated that it’s because they are busy caring for children etc. Perhaps now, we can simply say that it’s not worth the risk, because if they aren’t researching the female body, we aren’t required for their research anyways.

Drug companies need female research subjects to get their drugs approved. We are the predominant market, and designing these trials for men is not only ignorant, unscientific, and unsafe, it’s also horrible for business. If women can’t be protected and considered in a clinical trial, conducted by the drug company, they shouldn’t be forecasting revenue from women.

How to Move Forward

Despite all of the problems in the research, and with Lykos Therapeutics, we still need new treatments for PTSD. Women are twice as likely to suffer from PTSD, and millions of women can benefit from new treatment options. MDMA can save lives, and the data did show that.

With adequate informed consent and labeling, adverse events - particularly in women - can be reduced. Dose reductions may be wise to consider, as there is a long standing history of women being overmedicated in the western medical system. This anecdote, combined with the aforementioned paper on MDMA, citing stronger effects in women, suggests that women may not need the same dose as a man.

Lykos, and other drug companies for that matter, can still make a commitment to study women and better understand the risk factors for their largest market. However, if we don’t pay attention to this now, MDMA and psychedelics in general, will follow suit with the systemic practice of overmedicating women, and leaving them at higher risk for adverse events.

The real difference here is that psychedelic drugs are under intense scrutiny, whereas other drug companies have been getting away with this quietly for years. Not considering women in research is a systemic problem in the drug development process, and is not isolated to psychedelic research.

Because of the history of women in research, trials have historically been male-biased, and there is a severe lack of research advancement and innovation in accounting for female specific variables such as menstrual cycle phase.

Moving forward, there is a tremendous opportunity for psychedelic trial redesign that incorporates the needs of women. Psychedelics are new to the western medical system, and there are numerous problems to be solved, including safety, therapy and blinding. Can’t we just add a bullet point for considering women to the mountain of other problems? This approach reminds me of the saying: ‘while you’re under the hood, can you fix this too?’.

Advancement and innovation in these key areas in psychedelic medicine can inform statistics and methods that can be shared and applied to scientific domains outside of psychedelic medicine. This approach can enhance the knowledge and understanding of cyclical female biology in broader clinical settings.

It would also help the psychedelic industry get more buy-in from their largest patient demographic, and potentially their biggest supporters - women.