MDMA (now known as midomaphetamine by the FDA) is a substituted amphetamine that was first synthesized in 1912 by Merck. Over the past three decades, the drug has been developed by the Multidisciplinary Association for Psychedelic Studies (MAPS) as a new approach to treating post-traumatic stress disorder (PTSD).
The drug is administered in three doses at least one week apart as part of a 14-week course of psychotherapy. Results from six Phase 2 trials as well as two large Phase 3 trials have confirmed marked clinical efficacy, even in patients who have not responded to other treatments. These data allowed the FDA to designate MDMA as a breakthrough therapy for the treatment of PTSD.
In response to the positive results, a company called Lykos was founded with the goal of bringing MDMA into medicine. The first step in this process will be the submission of a clinical efficacy and safety dossier to the US FDA, where a decision is expected in August 2024.
In early June 2024, the FDA held a public advisory committee (AdCom) hearing that almost unanimously rejected the evidence presented by Lykos on the efficacy and benefit-to-risk ratio of MDMA-assisted therapy (MDMA-AT).
This decision surprised many experts in the field, especially since the clinical efficacy data had been published in peer-reviewed, high-quality journals and seemed to meet FDA requirements that two placebo-controlled randomized controlled trials (RCTs) be required to confirm efficacy.
Moreover, new approaches to the treatment of PTSD have been urgently needed for decades, as it has been almost 30 years since the licensure of two antidepressants from the SSRI group, and they rarely provide complete remission.
An additional clinical advantage of therapy with MDMA is that the drug is administered only three times during treatment, unlike other psychiatric drugs such as SSRIs, which are prescribed for long periods of time and carry a constant risk of side effects.
This decision surprised many experts in the field, especially since the clinical efficacy data had been published in peer-reviewed, high-quality journals and seemed to meet FDA requirements that two placebo-controlled randomized controlled trials (RCTs) be required to confirm efficacy.
Moreover, new approaches to the treatment of PTSD have been urgently needed for decades, as it has been almost 30 years since the licensure of two antidepressants from the SSRI group, and they rarely provide complete remission.
An additional clinical advantage of therapy with MDMA is that the drug is administered only three times during treatment, unlike other psychiatric drugs such as SSRIs, which are prescribed for long periods of time and carry a constant risk of side effects.
This approach is seen as a significant advancement because it reduces the overall impact of the medication on the body, reducing the risks of drug interactions, allergies and tolerance development, as well as potential withdrawal symptoms. In addition, a limited schedule of administration can result in significant long-term savings for the health care system by reducing the ongoing costs of treatment.
The data provided meets FDA requirements that two placebo-controlled trials be conducted to demonstrate efficacy and a positive benefit-to-risk ratio, which is what Lykos' data demonstrated.
The effect size for MDMA therapy was approximately 1 [large effect size], which is three times larger than that for the only class of licensed drugs for the treatment of PTSD, the SSRIs (fluoxetine, sertraline, venlafaxine, and paroxetine).
It should be noted that the between-subjects effect size subtracts the effect of standard therapy from the total effect of therapy plus MDMA, leaving only the effect of MDMA. The within-subjects effect size is more significant, which was 2.1 in the MAPP1 study and 1.95 in MAPP2.
The data provided meets FDA requirements that two placebo-controlled trials be conducted to demonstrate efficacy and a positive benefit-to-risk ratio, which is what Lykos' data demonstrated.
The effect size for MDMA therapy was approximately 1 [large effect size], which is three times larger than that for the only class of licensed drugs for the treatment of PTSD, the SSRIs (fluoxetine, sertraline, venlafaxine, and paroxetine).
It should be noted that the between-subjects effect size subtracts the effect of standard therapy from the total effect of therapy plus MDMA, leaving only the effect of MDMA. The within-subjects effect size is more significant, which was 2.1 in the MAPP1 study and 1.95 in MAPP2.
The MDMA effect becomes even more significant given that many participants in the MAPS trials were treatment resistant, that is, did not show an adequate response to both SSRIs and psychotherapy, which is typical of a significant group of people with PTSD.
The high statistical significance of the clinical results raised questions among some experts who voted against the therapy, perhaps because of doubts unrelated to statistics. This may be due to the uniqueness of this treatment, which alarmed AdCom committee members.
AdCom consumer representative Kim Witczak expressed, «This is new territory and caution is needed; it's important to be vigilant now». However, being overly cautious could deny suffering patients access to medical therapies that could significantly improve their lives.
FDA AdCom's main concerns
We summarize the 7 key concerns raised at the FDA AdCom hearing in Table 1 below. Each of these concerns can be addressed, as we outline in the next section. None of them by themselves should prevent MDMA therapy, although the accumulation of doubts about each of them may explain the advisory panel's votes. As Oreskes and Conway note in their book Merchants of Doubt, the creation of doubt is a common way in which scientific facts are undermined in people's minds, making policy decisions less straightforward.
The high statistical significance of the clinical results raised questions among some experts who voted against the therapy, perhaps because of doubts unrelated to statistics. This may be due to the uniqueness of this treatment, which alarmed AdCom committee members.
AdCom consumer representative Kim Witczak expressed, «This is new territory and caution is needed; it's important to be vigilant now». However, being overly cautious could deny suffering patients access to medical therapies that could significantly improve their lives.
FDA AdCom's main concerns
We summarize the 7 key concerns raised at the FDA AdCom hearing in Table 1 below. Each of these concerns can be addressed, as we outline in the next section. None of them by themselves should prevent MDMA therapy, although the accumulation of doubts about each of them may explain the advisory panel's votes. As Oreskes and Conway note in their book Merchants of Doubt, the creation of doubt is a common way in which scientific facts are undermined in people's minds, making policy decisions less straightforward.
Table 1 Key concerns raised during the FDA AdCom hearings
Regulation of combination therapy | How can a combination of medicine and psychotherapy be regulated when the FDA has no jurisdiction over psychotherapy? | |
Blinding issues | Could the failure to blind patients to the active MDMA arm, combined with an expectancy of positive results in the MDMA treated group have biased the results? | |
Potential for misuse | Given MDMA popularity as a recreational drug, could its misuse increase if it were approved as a medicine? A related concern appeared to be the fear that patients might seek out MDMA after enjoying its effects during therapy. | |
Training and generalizability | It would be difficult to train enough psychiatrists and other therapists to ensure the generalizability of treatment efficacy outside of clinical trials. | |
Risk of therapists' misconduct | Is there a risk of therapists breaking down personal boundaries, potentially encouraging sexual contact between patients and therapists. | |
Long-term benefits | What are the long-term benefits of MDMA-assisted therapy, and how can they be assessed? | |
Negative benefit-risk ratio |
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Solutions to key problems
In the MAPS psychotherapy program, MDMA is being tested as a tool to help PTSD patients process the strong emotions associated with trauma. Neuroimaging studies confirm that MDMA can reduce depression when traumatic experiences are reactivated, making it a useful adjunct to standard extinction-based psychotherapy.
In the MAPS psychotherapy program, MDMA is being tested as a tool to help PTSD patients process the strong emotions associated with trauma. Neuroimaging studies confirm that MDMA can reduce depression when traumatic experiences are reactivated, making it a useful adjunct to standard extinction-based psychotherapy.
Combining medication with psychotherapy is a common practice in psychiatry. Studies show that such a combination, such as antidepressants with therapy, has a positive effect on the treatment of depression. In the treatment of anxiety disorders, the use of different drugs improves the results of exposure therapy, as has been the case with benzodiazepines in the past and with d-cycloserine in recent studies.
For PTSD, paroxetine and yohimbine have been found to enhance the efficacy of exposure therapy, although combination therapies have not yet been approved for this group of disorders. Requests for combination therapy with MDMA have not previously been made, unlike nalmefene, which received EMA approval in 2013 for the treatment of alcoholism, and the recent approval of escetamine for treatment-resistant depression.
Esketamine is an interesting example because it has similar properties to MDMA and ketamine, and causes more pronounced changes in consciousness. This has influenced FDA requirements for the use of esketamine related to safety and patient monitoring [usually several hours].
Both drugs, including ketamine, have the potential for abuse and addiction, but ketamine is less strictly controlled than MDMA. Ketamine is freely used «off-license» to treat a variety of mental disorders, while MDMA requires special permission for research.
Ketamine was originally used to treat addiction and resistant depression and is now being actively investigated in combination with psychotherapy. However, many clinics use ketamine and esketamine without appropriate therapy.
For PTSD, paroxetine and yohimbine have been found to enhance the efficacy of exposure therapy, although combination therapies have not yet been approved for this group of disorders. Requests for combination therapy with MDMA have not previously been made, unlike nalmefene, which received EMA approval in 2013 for the treatment of alcoholism, and the recent approval of escetamine for treatment-resistant depression.
Esketamine is an interesting example because it has similar properties to MDMA and ketamine, and causes more pronounced changes in consciousness. This has influenced FDA requirements for the use of esketamine related to safety and patient monitoring [usually several hours].
Both drugs, including ketamine, have the potential for abuse and addiction, but ketamine is less strictly controlled than MDMA. Ketamine is freely used «off-license» to treat a variety of mental disorders, while MDMA requires special permission for research.
Ketamine was originally used to treat addiction and resistant depression and is now being actively investigated in combination with psychotherapy. However, many clinics use ketamine and esketamine without appropriate therapy.
Despite the increased interest in combining ketamine and psychotherapy, no regulatory agency has received an application for approval of this approach, likely due to the difficulty of patenting. Lykos' presentation to the FDA for the combined use of MDMA and psychotherapy would be the first case of its kind, creating uncertainty for regulators due to the lack of precedent.
Blinding and waiting
During the hearing, the discussion of disclosure was an important topic. This is surprising since the MAPS design has previously received FDA approval, and blinding is not considered a critical issue in trials of other drugs. A recent study of PTSD treatment found that blinding was not evaluated in most trials, although some drugs were approved based on significant clinical effects.
Ketamine and esketamine, which also have psychoactive properties, have met similar difficulties. Their trials were not blinded, but this did not prevent esketamine from being licensed. This raises questions about biases against esketamine and MDMA in the context of PTSD. Such biases were initially noted in reviews of MDMA and psilocybin in Australia, but were corrected in the TGA decision.
The problem of blindness and expectations relates to the misunderstanding that knowledge of receiving MDMA or psilocybin may improve outcomes even if the therapeutic activity of the drug is absent, creating a super placebo effect. However, this is unlikely: many patients with PTSD have not responded to previous treatments, suggesting different expectations about MDMA. Waiting effects are also difficult to achieve with other drugs.
The question arises as to whether patients actually exaggerated their response to MDMA. Some patients reported being «supported» in their positive attitudes toward treatment, but it is unclear whether this was true for everyone receiving MDMA. It is likely that management did not believe in the sincerity of patients who reported significant improvements and assumed that too many were still engaging in bad behavior.
The question arises as to whether patients actually exaggerated their response to MDMA. Some patients reported being «supported» in their positive attitudes toward treatment, but it is unclear whether this was true for everyone receiving MDMA. It is likely that management did not believe in the sincerity of patients who reported significant improvements and assumed that too many were still engaging in bad behavior.
The board may also have failed to consider what mechanism might have explained the MDMA group's better results: the effects of the drug, psychotherapy, or a combination of the two. Psychotherapy was standard in both groups, which rules it out as the only factor. Sustained results may require a combination with psychotherapy, as without it the treatment of severe trauma would be unethical and potentially dangerous.
It is clear from the testimony about the value of psychotherapy to patients that without it, outcomes could be significantly worse, including in the example of surgery without anesthesia. Thus, a trial without psychotherapy would be inappropriate and probably impossible because of the patients' refusal to participate in such a group.
It is clear from the testimony about the value of psychotherapy to patients that without it, outcomes could be significantly worse, including in the example of surgery without anesthesia. Thus, a trial without psychotherapy would be inappropriate and probably impossible because of the patients' refusal to participate in such a group.
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