Yves here. As this article points out close to the top, MDMA, aka ecstasy, is not a psychedelic but an amphetamine, so it’s peculiar to see a site like The Conversation that publishes articles by academics mislabel it in its headline, which we have reproduced above. Is this because the promoters of psychedelics as potential mental health treatments are keen to tout any breakthrough FDA approval, even if not really in their category, as validation?
Keep in mind that once a drug is approved by the FDA, it can be prescribed for other “off label” uses. For instance, Botox sales consist almost entirely of off label Rxing. So there’s an argument that being too free with the approval of mental condition drugs can promote over-use, as seen with Adderall. The issue with this FDA MDMA new drug application rejection apparently was due to less than persuasive results and deficiencies in study design, which in-the-pipeline applications for the therapeutic use of bona fide psychedelics supposedly remedy.
By Benjamin Y. Fong, Honors Faculty Fellow, Associate Teaching Professor, and Associate Director of the Center for Work & Democracy, Arizona State University. Originally published at The Conversation
Drugmaker Lykos Therapeutics announced on Aug. 9, 2024, that the Food and Drug Administration declined to approve the company’s application for the use of MDMA-assisted therapy in the treatment of post-traumatic stress disorder. It is the first such decision issued on a psychedelic drug application.
Many investors and researchers have been predicting a psychedelics boom, with MDMA being just the first of a number of psychedelics in the drug development pipeline.
The FDA’s decision has disappointed psychedelic therapy advocates, and the stock prices of psychedelic industry leaders tumbled with the announcement. But the FDA did make recommendations as to how the application could be improved in such a way that MDMA might receive future approval.
Yet another setback came days later when the journal Psychopharmacology retracted three papers related to MDMA-assisted therapy, citing “protocol violations amounting to unethical conduct,” particularly in one clinical trial.
What is MDMA, and What Types of Conditions Could It Treat?
MDMA, or midomafetamine, is known colloquially as “molly” or “ecstasy.” It is technically an amphetamine – like the drug in the attention-deficit/hyperactivity disorder medication Adderall – but MDMA is often categorized as a psychedelic. It is considered to be more pleasure-inducing than other amphetamines, and for this reason it has been a popular party drug. Some researchers call MDMA an “empathogen,” or a “feeling enhancer.”
While MDMA is currently a Schedule I drug – meaning that the Drug Enforcement Administration considers it to be highly dangerous with no accepted medical use – a number of clinical trials point to the benefits of using MDMA in combination with talk therapy for patients suffering from PTSD. The FDA granted “breakthrough therapy” status to MDMA-assisted therapy in 2017, which sped along its development and review.
PTSD affects between 9 million to 13 million people annually in the U.S., and no novel treatments for the condition have been developed in the past 20 years.
Lykos Therapeutics filed an application for FDA approval of its version of MDMA-assisted therapy for PTSD in February 2024. In it, the drug is paired with a type of psychotherapy intended to bring out a patient’s “inner healing intelligence”, which Lykos defines as “a person’s innate capacity to heal the wounds of trauma.”
Why Did the FDA Decline Approval of Lykos’ MDMA-Assisted Therapy?
In June 2024, an FDA advisory committee voted overwhelmingly against the idea that the relevant clinical trials had proved the efficacy of MDMA for the treatment of PTSD. Just as decisively, the panel also voted against the idea that the benefits had been shown to outweigh the risks, such as increased blood pressure and abuse potential.
At that time, the advisory committee took issue with several aspects of Lykos’ application. First, it noted the problem of “functional unblinding,” which is the fact that most people participating in the trial would know if they are on a powerful psychoactive substance or not, biasing the results. This is a problem for any psychoactive medication, and Lykos critics believe the company should have followed FDA guidance that it use an “active placebo” – a placebo that also has psychoactive effects – for comparison in its previous clinical trials.
The panel also raised questions about the form of psychotherapy used alongside MDMA, as well as ethical concerns about various forms of misconduct in Lykos’ trials. In one of the company’s studies, a participant reported sexual misconduct by the therapists involved.
The FDA is not bound by the votes of such advisory bodies, but it typically follows their guidance. So the decision on Friday was no great surprise.
What Does the FDA’s Decision Mean for the Future of MDMA?
The FDA requested an additional phase 3 study, the stage of clinical trials that rigorously demonstrates the safety and efficacy of a particular treatment in comparison to standard treatment.
Lykos stated that it will request a reconsideration of the decision and discuss the FDA’s recommendations with the agency to ensure that the company is on the right path forward.
Lykos CEO Amy Emerson, who called the decision “deeply disappointing,” says she believes it will take “several years” to conduct the new trial.
But with the journal Psychopharmacology’s retraction of three papers related to this work, Lykos has a difficult road ahead of it.
How Might This Decision Affect Other Psychedelic Drugs’ Approval?
One prominent psychedelics company, Compass Pathways, is generally considered next in line for FDA approval of a psychedelic drug, with phase 3 clinical trials for its synthetic psilocybin well underway. There are other companies preparing for phase 3 trials of their own proprietary compounds.
In the wake of the advisory panel judgment in June, Compass noted that it is not pairing its drug with therapy in the way Lykos has. Another company claimed that it has a “better trial design that is more in line with FDA guidance.”
Other psychedelics companies clearly believe they can still succeed where Lykos has not.
Do Psychedelics Face Unique Challenges?
The FDA’s decision was more about Lykos’ specific approach than an outright rejection of psychedelics for therapeutic use.
But psychedelic drug development is a fraught process by nature. The drugs involved induce a severely altered state that puts people in a vulnerable position. Some people in the industry that I have spoken to believe it’s nearly impossible to avoid accusations of impropriety, given the nature of the experience.
Most research also pairs psychedelic drugs with some form of therapy or facilitation, and as the FDA has made clear, its role is to assess drugs, not the psychotherapies that might go along with them.
The interaction between the drugs and the human element involved in the treatment is the subject of some debate. Lykos’ missteps in its application shine a light on some of the ways that companies involved in psychedelic drug development face unique obstacles on the way to FDA approval.
I can’t speak comprehensively for the utility of MDMA in the treatment of PTSD, I can however speak to it as an effective ‘treatment’ for autism (a condition which at the milder end certainly is highly contingent on the adaptive capacity of society in general, which considering the cost of living and housing crisis has declined severely in the past 20 years), in that reductively it compensates for the sub optimal serotonin processing of people with autism and can help to a phenomenal degree with processing emotions and facilitating social bonding individuals with autism may struggle with, far superior to (in my experience) to SSRAs given out to treat anxiety/depression. It’s is worth pointing out research shows the life expectancy of individuals with autism ranges from the 30’s-50’s, the causes for this are quite variant (ranging from poor health, to higher rate of suicide to a propensity for getting into accidents), but a substance that allows for such people to both enjoy life more and can assist in allowing them to form social bonds they might otherwise not be able to would potentially go some way to ameliorate this.
Re Bad editors at Conversation. Yves, your surprise at the mistake in the title of the original article is unfortunately (IMO) not misplaced but may be due to simple incompetence + bad editing at The Conversation.
I have published once in The Conversation and it was not an experience I ever wanted to repeat. Their “discipline specific editors” are (in my experience and that of a couple of peers in other realms) very variable. In my experience preconceptions were brought to the table in attempting to edit the article I and a co-author (who was one of the “top three” in the field) wrote, which would have fundamentally changed what we were saying.
I came out of it all feeling that The Conversation has (surprise surprise) an agenda or agendas depending on which (sub)editors you get – so maybe your suspicions are correct(!) If I wanted to be charitable, I could point out that the pharmacodynamics of a lot of “amphetamine-adjacent” medications are still being amended decades after their discovery. One MAOI anti-depressant was for yonks assumed to be metabolised to something methamphetamine-related but I see no mention of that in more recent clinical papers and if I understand correctly, this has been discounted.
re drug names: Fans of actor Mark Heap might like the latest show he’s in which discusses drug names in episode 1 (which is all I’ve watched so far) – “Piglets” on UK ITVX streaming. I would watch him paint a wall and then watch it dry (which is close to one of the things he did in the first role I watched him act – “Spaced”).
Anyone who is aware of the brilliance of Green Wing should pay attention. I got a (ridiculously belated) suggestion on my phone to watch this new show. Some of the writers started out on Green Wing (which is good) and Heap plays major role (even better). The writing in episode 1 is a bit hit and miss but you can spot how certain writers know EXACTLY how to make this guy steal a scene – listing the drugs like meth made me really laugh.
I hope the rest of the season holds up because this guy should never ever not be on TV. End of tangent.
I used to work at the first center using Ibogaine for emotional transformation and trauma work. We ran a residential program involving 1 dose of ibogaine followed by 30 days group and individual therapy. It was the best thing I’ve ever been involved in. Over the time I was there I saw a lot of amazing healing and change in pretty much everyone that came through. I’m in touch with many of the people to this day, and the change was permanent. Examples of things people were able to heal: sexual trauma, complex PTSD, long-term abuse and addiction.
I’ve also a fair amount of positive experience of both MDMA and shrooms for healing work. Ayahuasca is something I’ve steered away from, although others seem to have found benefit from it.
I’m a huge proponent of the power of hallucinogens. However they are also dangerous. Ibogaine specifically can kill you (although this is less a risk for emotional work as the dose is lower than used to treat heroin addiction). More relevant to the current US debate is the need for real care and nurture of clients. Deep change can be bewildering at first, and the integration period is very important. The 30 days our clients stayed with us were vital.
I’m aware of many people who have had issues doing hallucinogen work without the proper support (or individual resilience). For some it really made things worse.
And so I have at best mixed feelings about what might come from a mainstreaming of these drugs.
I have zero faith in the Western psychology model being able to successfully integrate psychedelic work. I will not clog up this reply with a rant about that.
Further, I am very skeptical that commercialisation will bring good things. As with other health areas, profit trumps care. We were successful, I believe, because we did our work with real love and care for our clients. I fear this will be lost in the same way commodification has ruined so many of the things I love and value.
YMMV
I think the confusion is in the audience rather than in the article but the problem is these things are taught properly in schools. Just say no, kids!
MDMA is an amphetamine. This is a term of chemistry. The molecular structure contains a phenylethylamine skeleton, which is the definition of an amphetamine. MDMA is 3,4-Methylene-Dioxy-MethAmphetamine . The amphetamine skeleton can have many permutations through the addition of side groups and the side groups affect the pharmacological activity. Crystal meth is an amphetamine and colours the popular view of all amphetamines (speed, “go” pills etc.) because it is almost exclusively a stimulant and works on the sympathetic nervous system.
The particular sidegroups of MDMA make it very different in effect (except at high doses) from crystal meth but it is still an amphetamine to a chemist, however customised. Pharmacologically, it affects the sympathetic nervous system but also the serotonergic nervous system. Among the latter effects are a flood of serotonin, which is believed to be responsible for the “loved up” alterations in mood and sensation (touch etc.) that makes MDMA the “love drug”. Users are jittery, energetic, chewing their jaws etc. from the speed-like effects but they also want to hug and talk, connect, open up. MDMA has been called an empathogen and an entactogen for these effects. MDMA is also noted as having mild hallucinogenic effects, with distortion of time and space and sound, perception of lights, peripheral versus central vision. You can see why it packs a punch in a nightclub! Depending on what people want from the drug, they vary the setting to intensify different effects – partygoers taking it at rave to get lost in music and the crowd versus a couple taking it on a sofa to get lost in each other.
As a result of its serotonergic effects, MDMA is also usually described as a psychedelic because it is capable of “manifesting the mind/ego” (the literal translation of psychedelic).
It is not commonly viewed as an hallucinogen in its own right, though: it has these effects especially at certain doses but they are somewhat “off-target” and there are much more powerful hallucinogens, even among the wider drug family MDMA belongs to.
If you want a reference for MDMA (and the class of related compounds) and their very unusual properties compared with crystal meth-type amphetamines, I would direct you to Alexander Shulgin and his masterworks, Phenylethyamines I have Known and Loved (Phikal).
Pihkal is a very unusal book. Half of it is a graduate level organic synthesis book; half of it is a pre-modern scientist’s discussion of the pursuit of knowledge in chemistry and pharmacology and his and his wife’s (FDA licensed) self-experimentation with psychedelics. It is, in some senses, like reading a great chef’s cookbook and memoir. It is fascinating book, even if you don’t have the chops to follow the chemistry.
Don’t forget the follow-up: TiKHAL (T=Tryptamines). As Revenant says, these books contain enough synthetic detail that an advanced undergrad/freshly minted grad could make the compounds, given starting materials and a fairly basic lab. I have a PhD in O Chem, and have worked on making various psychedelic derivatives based on trimethoxybenzene (mescaline is the trimethoxy analogue to MDMA).
Both books are available from Synergetic Press, as well as Shulgin’s two other main books, The Nature of Drugs, Vols 1 and 2, based on his 1987 lectures at SFSU.
Your post appeared along with mine. Tryptamines are the “other half” of what I want to say, so thanks for bringing them up.
Wish I’d had this comment in 2010 when I had to make decision as to an MAOI!
Thank you. It is very frightening that of mental health professionals, only (IMHO) 2-5% understand things like MAOIs and amphetamines, and only 25% of those have enough pharmacological knowledge to make an informed judgment as to whether the patient in front of them might stand a chance of benefiting.
I still firmly believe amphetamine has a role in mental health. However I am equally sure that we don’t understand WTF role it has in anything but some very extreme cases. Serious resources are required to investigate this.
But hey – why not just milk Medicare or the NHS by throwing Adderall etc at the problem? /sarc
I have taken MDMA twice in a therapeutic setting with an underground therapist. It is very powerful and it has been an important part of my ongoing therapy. As others have pointed out – it is technically not a psychedelic but it acts like a psychedelic in that it gives patients access to memories, feelings, and insights that they would not otherwise be able to access.
I was talking to my therapist about the push to legalize psychedelics that is coming from the veterans community – which is in dire need of effective treatments. She said, her voice dripping with bitterness, “What are they going to do? Say ‘f*ck the veterans’?”.
So far it seems the answer is “yes”.
Drugs are nowhere to be seen @ Burning Man, but obviously with so many frenzied smiles, something is amiss and molly ain’t my bag as i’m strictly mister natural, but it seems to be quite popular around those parts.