Risks of MDMA abuse
Another issue raised by the group was the fear of MDMA abuse and dependence, which is summarized below
(see below and Table 1).
DHHS has a checklist of eight factors to determine risk of abuse:
- The actual or relative abuse potential of the drug.
- Scientific evidence of its pharmacologic effects, if known.
- The state of current scientific knowledge about the drug or other substance.
- Its history and current pattern of abuse.
- The extent, duration and significance of abuse
- What risk, if any, is there to public health?
- Its propensity for mental or physiologic dependence.
- Whether the substance is a direct precursor to an already controlled substance.
Table 1. MDMA addiction risk from three positions
Data from the recent MDMA trials | Data from recreational use of MDMA/ecstasy | The psychopharmacology of MDMA in comparison with other drugs of abuse |
In the last three decades, MDMA therapy has been studied extensively as a treatment for PTSD, which has now completed phase 3 development and is currently awaiting licensing decision from the FDA. Smaller pilot studies have also examined the potential role of MDMA therapy in treating addictions (specifically Alcohol Use Disorder (AUD)) and Social Anxiety Disorder in adults with autism. The phase 3 trial by Mitchell et al (Nicholas et al. (2022)) in patients with severe PTSD did not show an increased risk of substance use or dependence among participants, as assessed by the Drug Use Disorder Identification Test (DUDIT) and Alcohol Use Disorder Identification Test (AUDIT). Specifically, there was no increased MDMA use observed during and 2 months following the treatment. In all the MAPS pilot, phase 2 and phase 3 studies of MDMA-PTSD, there have been no cases of participants craving MDMA or exhibiting drug-seeking behaviours following participation in trials. Also, data from a study of MDMA- in patients with an addiction (AUD) demonstrated the same lack of evidence of MDMA addiction following treatment in the trial (Sessa et al 2021). | There is a high prevalence of use of ecstasy in UK – second only to cannabis, with an estimated 800,000 MDMA users every week in the UK. This high figure contrasts starkly with the very low reporting of MDMA as the primary drug of abuse in UK addiction treatment centres. Only 424 such cases were reported in community drug services, and zero cases of MDMA were cited as the primary drug of addiction in UK residential treatment centres. This compares favourably with other ‘new’ recreational drugs (cathinones, ketamine), which within 12-months of appearing on the recreational drug scene, saw multiple cases of addictions in community and residential rehab centres in the UK. The Global Drug Survey (GDS) estimates that around 2-3% of MDMA users use it on a continuous basis, similar to ketamine (GDS 2022). | MDMA primarily releases serotonin with minimal dopamine release compared to substances with higher addictive potential, suggesting it may not produce the same reinforcement mechanisms that contribute to addiction in drugs like cocaine, opioids, or nicotine. This is likely due to lower activation of the brain's dopamine system, which is associated with compulsive drug-seeking behaviour and addiction. Additionally, serotonergic psychedelics have low/no dependence propensity and indeed can be used to treat addiction. |
Concerns that euphoria during MDMA therapy may explain the therapeutic effects and attract non-patients are unfounded. As a MAPS participant noted, therapy is often not enjoyable: «I don't know why they call it ecstasy». MDMA is only used three times, which reduces the likelihood of addiction.
Long-term recreational use of MDMA shows a low risk of addiction, as evidenced by the National Institute on Drug Abuse (NIDA), which calls it «potentially» addictive. Recent studies have not confirmed an increase in MDMA use following therapy, nor has there been an increase in the use of other drugs.
The need for a fair assessment of MDMA may be distorted by its illicit status and negative public opinion. Independent expert analysis has shown that harms from MDMA are lower than most other recreational drugs, including alcohol and opioids. Although the effects of getting high are more pronounced with opioids, many are legalized. This may indicate a stigma towards mental health disorders such as PTSD. Even if medical MDMA were to hit the black market, the risks would be lower than from opioids.
The need for a fair assessment of MDMA may be distorted by its illicit status and negative public opinion. Independent expert analysis has shown that harms from MDMA are lower than most other recreational drugs, including alcohol and opioids. Although the effects of getting high are more pronounced with opioids, many are legalized. This may indicate a stigma towards mental health disorders such as PTSD. Even if medical MDMA were to hit the black market, the risks would be lower than from opioids.
Similar choices have already been made for other drugs with high abuse potential, such as amphetamines for ADHD, dopamine agonists, and ketamine for depression. NIDA is also investigating the use of ketamine for addiction, which may make further research difficult.
It is critical to focus on assessing risk and benefit rather than patient fears. Approving MDMA as a medicine could undermine existing anti-policy rhetoric.
In more than 2000 therapeutic cases, no dependence on MDMA has been reported. That said, despite the popularity of recreational use in the UK over 40 years, referrals remain low and levels of use are almost unchanged. The low risk of dependence is likely due to MDMA's unique serotonergic profile.
Therapists' risk of misconduct: breach of boundaries
MDMA therapy requires deep interaction between patient and therapist, and each session can last up to 8 hours, which creates difficulties and increases the risk of transference, amplified by MDMA's effects on empathy and trust. Similar risks exist with other psychedelics such as psilocybin.
The MAPS program faced criticism after a clinical negligence incident in which an intimate relationship developed between a patient and therapist. Although this was an isolated incident, it has been used to question the reliability of MDMA therapy.
Nevertheless, such violations should not devalue a new class of therapy. Improvements can be made by recording and analyzing sessions to improve quality and responsiveness to complaints. Additionally, MDMA therapy is no more risky than other types of psychotherapy. Unfortunately, there is a lack of general transparency about the potential harms of psychotherapy, but the use of two therapists in MAPS significantly reduces these risks.
MDMA therapy requires deep interaction between patient and therapist, and each session can last up to 8 hours, which creates difficulties and increases the risk of transference, amplified by MDMA's effects on empathy and trust. Similar risks exist with other psychedelics such as psilocybin.
The MAPS program faced criticism after a clinical negligence incident in which an intimate relationship developed between a patient and therapist. Although this was an isolated incident, it has been used to question the reliability of MDMA therapy.
Nevertheless, such violations should not devalue a new class of therapy. Improvements can be made by recording and analyzing sessions to improve quality and responsiveness to complaints. Additionally, MDMA therapy is no more risky than other types of psychotherapy. Unfortunately, there is a lack of general transparency about the potential harms of psychotherapy, but the use of two therapists in MAPS significantly reduces these risks.
It is also important to assess the safety of alternative psychotherapies for the treatment of PTSD. Prolonged exposure therapy is effective, but many patients cannot tolerate it, resulting in more than 50% treatment failure. In contrast, MDMA can help patients stay in therapy and achieve better outcomes.
Uncertain long-term benefits
This issue arises with all new medicines where funding constraints or necessity preclude very long term studies. These are usually conducted as Phase 4 studies after marketing authorization. MDMA therapy should not be considered differently, especially as there is already 20 years' experience of its use in Phase 2 equivalent clinical trials showing evidence of sustained efficacy over several years.
Negative benefit to risk ratio
The results of the vote, in which 9 of 11 participants found MDMA treatment to be ineffective, were not unexpected, as the group then voted 10-1 that the benefit-to-risk ratio was negative. However, the approach taken to risk assessment was questionable.
Uncertain long-term benefits
This issue arises with all new medicines where funding constraints or necessity preclude very long term studies. These are usually conducted as Phase 4 studies after marketing authorization. MDMA therapy should not be considered differently, especially as there is already 20 years' experience of its use in Phase 2 equivalent clinical trials showing evidence of sustained efficacy over several years.
Negative benefit to risk ratio
The results of the vote, in which 9 of 11 participants found MDMA treatment to be ineffective, were not unexpected, as the group then voted 10-1 that the benefit-to-risk ratio was negative. However, the approach taken to risk assessment was questionable.
The Administrative Committee (AdCom) was called upon to provide a binary yes-no vote on both the efficacy and benefit-to-risk ratio of MDMA, which is an inappropriate practice for a complex and novel treatment. Instead, it would be worthwhile to provide a confidence level assessment for each committee member to make a decision.
The best option would be to use one of the current benefit-risk analysis methodologies or to conduct a full multiple criteria analysis (MCDA) as was developed for EMA.
To request a specialized committee to consider complex issues concerning a new drug and its treatment regimen in a single-stage hearing is a simplification, calling into question the validity of the opinions.
The best option would be to use one of the current benefit-risk analysis methodologies or to conduct a full multiple criteria analysis (MCDA) as was developed for EMA.
To request a specialized committee to consider complex issues concerning a new drug and its treatment regimen in a single-stage hearing is a simplification, calling into question the validity of the opinions.
In sum, it appears that the experts' opinions were based on several circumstances. First of all, there was a clear fear associated with new drugs, especially in the field of psychiatry, leading to excessive caution and a search for reasons to refuse.
These fears were dictated by regulatory authorities, which raised many different doubts, none of which individually would have been sufficient to block a positive decision, but collectively created sufficient uncertainty to support a negative vote.
What's next?
The decision is now up to the FDA, which is approaching the final stage of the decision-making process. They can ignore the panel's recommendations, and we hope this analysis will be helpful to them. The FDA's rejection of Lykos' application will lead to further difficulties.
The existing serious need for new and effective treatments for PTSD will continue, and many patients will likely continue to suffer, which could lead to suicide, or begin to seek less safe alternative therapies.
These fears were dictated by regulatory authorities, which raised many different doubts, none of which individually would have been sufficient to block a positive decision, but collectively created sufficient uncertainty to support a negative vote.
What's next?
The decision is now up to the FDA, which is approaching the final stage of the decision-making process. They can ignore the panel's recommendations, and we hope this analysis will be helpful to them. The FDA's rejection of Lykos' application will lead to further difficulties.
The existing serious need for new and effective treatments for PTSD will continue, and many patients will likely continue to suffer, which could lead to suicide, or begin to seek less safe alternative therapies.
Science has faced similar situations in the past, as with the first HIV drugs, access to which was delayed, leading to lobbying for an expedited approval process by the FDA and additional research by the NIH.
In the case of the denial of MDMA sales, a possible analogy to the decision by the U.S. Department of Health and Human Services (DHHS) in August 2023 to move cannabis from Schedule I to Schedule III. This decision was based on an analysis that showed cannabis met the criteria for medical use and should not remain in Schedule I. The current evidence for MDMA for the treatment of PTSD is probably more compelling than for any medical cannabis product, which could lead to a similar decision as in Australia.
In the case of the denial of MDMA sales, a possible analogy to the decision by the U.S. Department of Health and Human Services (DHHS) in August 2023 to move cannabis from Schedule I to Schedule III. This decision was based on an analysis that showed cannabis met the criteria for medical use and should not remain in Schedule I. The current evidence for MDMA for the treatment of PTSD is probably more compelling than for any medical cannabis product, which could lead to a similar decision as in Australia.
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