Dr. Howard Kornfeld on the Future of MDMA-Assisted Therapy

Dr. Howard Kornfeld, MD is among those rare clinicians who is both a pioneer in psychedelic medicine and an expert in the treatment of addiction. He convened early investigators with FDA approved studies in pivotal research and organized policy conferences—the 1994/1995 Pacific Symposia on Psychedelic Drugs—while serving as a visiting physician-in-residence at the Esalen Institute. 

Board certified in Emergency Medicine for 40 years, Dr. Kornfeld serves on the clinical faculty and has taught in the pain and addiction fellowship and other programs at UCSF. 

He is nationally recognized as a lead advocate for the use of buprenorphine, also known as Suboxone, for chronic pain and opiate addiction. 

Dr. Kornfeld is a Diplomate in Pain Medicine, recognized by the American Board of Psychiatry and Neurology, and a Distinguished Fellow of the American Society of Addiction Medicine. Considered an expert in alcohol, benzodiazepine, cocaine, and stimulant addiction, Dr. Kornfeld developed his treatment approach and built a practice at Recovery Without Walls in Mill Valley, CA which has served as a model for outpatient care.  

On August 6, 2024 Dr. Kornfeld published an open letter in Lucid News to Robert M. Califf, MD, Commissioner of Food and Drugs at the FDA, concerning the administration’s imminent decision on whether to approve the Lykos Therapeutics proposal for MDMA-assisted therapy for PTSD. “I am writing to endorse midomafetamine-assisted therapy for PTSD because I believe that the benefits outweigh the risks,” wrote Kornfeld.

In his letter, Kornfeld cited his long familiarity with the opiate crisis and with the life saving potential of buprenorphine. He noted that buprenorphine was invented in the late 1960s, but did not achieve FDA approval for the treatment of opiate use disorder until 2002. Kornfeld wrote that the history of FDA approval of buprenorphine could help frame the upcoming FDA decision on MDMA-assisted therapy for PTSD. 

Kornfeld noted that a favorable decision on buprenorphine was made by the FDA despite known risks, including instances internationally of buprenorphine abuse. “The FDA also approved buprenorphine despite both the stigmatization of the medication strategy itself and the population with opioid use disorder it would serve,” wrote Kornfeld. “The development of buprenorphine, as hopefully will happen with MDMA, progressed successfully: a shining example of private/public/regulatory partnerships which elevated the public health of the American people.”

Kornfeld’s letter also observed that in his decades of practice, he has treated many hundreds of patients with histories of misuse issues with a range of drugs. While many, if not most of his patients in particular demographics reported having used MDMA, Kornfeld wrote that he saw “very infrequent instances where the past use was noted as problematic, and in no case was any medical intervention required for recovery.”

Lucid News talked with Dr. Kornfeld about the subsequent FDA decision to deny the Lykos Therapeutics New Drug Application for MDMA-assisted therapy for PTSD. He offered his thoughts about the decision and the implications of Lykos potentially completing another Phase 3 study. 

Below are highlights of that conversation edited and condensed for clarity. In Part 2 of my conversation with Dr. Kornfeld, we discuss his thoughts about growing concerns about ketamine dependency and challenges presented by ketamine therapy delivery systems. 

In your open letter to Dr. Robert Califf regarding the then-pending decision about MDMA-assisted therapy for PTSD, you wrote that the benefits of the therapy outweigh the risks. Do you still believe that and what are your thoughts about the FDA decision? 

I have thought a lot about it since that fateful August 11th decision. And I still stand by my letter fully in every part. But I’ve done some additional thinking about the subject based on commentary that I’ve read. I think the FDA would have better served the American people and the public health had they approved this because we have an epidemic going on. Just like when COVID was killing people and they approved things on an emergency basis, without the full length of study that would normally have been done.

My sense is that PTSD is a national and world crisis. We live in a very traumatic world. If we don’t use every tool that we have to help people overcome trauma, we reduce our chances of avoiding more illness in this society and mental illness and more breakdown will increase.

And yet I also understand why I believe the different advisory panels were pushing the FDA to reject the MDMA application, the Lykos application. I’ve done some thinking based on my own background in the field of addiction medicine – and also as an observer of pharmacology in general – about how pharmacology, particularly a new and needed drug, might be introduced and approved.

There’s one paragraph in the letter where I focus on the drug that I’ve played a big role in as an early adopter. It’s called buprenorphine and it’s a life saving drug for people with opiate use disorder. We used to call it heroin addiction, or fentanyl addiction, or oxycontin addiction, and now we have this term, opiate use disorder.

When I started practicing addiction medicine some 30 plus years ago, we did not have buprenorphine. It was in clinical trials and it was a huge project to get this drug approved even though it had shown great promise. This was in the early 1990s that I started practicing addiction medicine.

And this drug had been invented, just like MDMA was invented, a long time ago. This drug had been invented in the late sixties and it was introduced initially as a pain drug analgesic in the early 1980s. But it wasn’t until the 1990s that they realized that it could be a life saving drug for opiate addiction, that enough work had been done.

France had adopted buprenorphine much earlier than we did. France adopted it seven years earlier. So we waited in this country seven additional years because we had different laws that had to be dealt with. We had a different process with the FDA. We had different groups that were opposed to the drug that felt it would just be another drug of abuse if it was brought out.

And we had, let’s say maybe people who were more involved with methadone. They didn’t want a new drug to come in that could disrupt what they thought was the best solution to the opiate addiction crisis. So there was a private company that had invented [buprenorphine] that still had some commercial prerogatives, partly because of some laws that were changed that allowed the drug company to still get a return on their investment. But there was a partnership between the drug company and the National Institutes of Health that realized they needed to sponsor.

So there was like a public private partnership to bring this drug buprenorphine to market. And it was a pretty complex process because laws had to be changed in every state because there were these archaic laws against the treatment of addiction, except in these methadone clinics. And so the National Institutes of Health sponsored a group of academic centers that did this research in collaboration with the company. And somehow in 2002, the FDA approved buprenorphine and it’s been one of the greatest approved drugs for public health, even though it’s still vastly underutilized.

So I was thinking about the parallels between buprenorphine and MDMA because the FDA did not approve it in this kind of easy way. I know that Lykos and other people are thinking of a new Phase 3 trial that would be designed to address the objections that were raised by the advisory committee and by this other group, the ICER [Institute for Clinical and Economic Review] group.

What decision from the FDA would have been better in your view?

I would have preferred if the FDA just approved it. Now they could have approved it with a lot of regulation in it. For example, when buprenorphine was approved, it was not available to any doctor to prescribe. A doctor had to take a course, a day or two-long course, in how to use it. And then they had to register with the Drug Enforcement Administration, with the DEA, to get a special little number. There was this awareness that it was a paradigm shifting drug, because up until that time, no doctor in their office could treat an opiate addiction only with an opiate.

There were only these methadone clinics, so it was such a shift of consciousness that was what it required to get it through. And now that it’s been around, all those special requirements have been lifted. Society saw that it wasn’t a threat, that it was actually a blessing if it was used properly.

So there’s efforts now to make it easier to prescribe and even, for example, to decriminalize it. So even if addicts on the street decide, “okay I’ll buy some buprenorphine and I’ll somehow get it started myself,” which is not recommended because it’s complicated, but yet it’s better than overdosing on fentanyl or street opiates like is happening right now. 

So with MDMA I could see how, in retrospect, these advisory committees saw that it was so different. Even the psychotherapy that was in the manual, it wasn’t like a standard “this is CBT [cognitive behavioral therapy] 101 that we’re going to do.” It was a very specialized therapy that was developed over the years by MAPS and by people in the community. But it was different, it was so different than what normally is provided. 

And every study has glitches and problems. But I think all these glitches and problems were magnified, in the eyes of these advisory committees. And then it seemed like there were too many things that were wrong.

You’ve noted that in the past, some doctors have been hesitant to prescribe opiates because they’re overreacting to the opioid epidemic. You’ve advocated for strong public health leadership. What public health guidelines do you propose for MDMA or other psychedelic assisted therapies? 

With MDMA, I was around back in the eighties when it first emerged in popular culture, before it was even scheduled. And so I was aware of the history of how it had been used. On that level, I share the sort of perspective of how MAPS organized the study. But in retrospect, given what we know now about how things can go wrong, even if they go wrong in a small number of things, patients or study subjects can be very vocal. 

And so one idea I had was that if research is being done and because these drugs are so powerful –  they can be powerful in a way of setting someone in the wrong direction. They can have powerful adverse effects in a small minority of patients.

So one thing that I think in retrospect should be built in is that if someone is in a study, that [they] actually are supported over a long period of time after the study. If they are suffering in some way or if they have a setback. I don’t think normally that drug companies do that. They don’t have the funds necessarily. But in the case of MDMA, and this might generalize to other psychedelics, there might be an obligation on the part of the study sponsor to provide meaningful support. Because MDMA is given to PTSD patients who are on an arc, a trajectory in their life. 

I don’t know exactly what the inclusion and exclusion criteria were around other medicines, but obviously it’s a very fragile population. There will be people who get a boost, but then may have a decline. But the way these studies are organized is once they’re in a decline, my understanding is that there are no longer resources available to help them through the company. There might be resources that they have in their own community, but those resources may need help because they have not dealt with a possible downturn that could happen weeks or months or years after an MDMA session. So that’s one thought I had that might inform future research.

The other thing is all this whole thing about the type of placebo arm to use. I read in some pieces in Psychedelic Alpha that came out last month or so talking about the issue of other options to an inert placebo. You can have a smaller dose of MDMA and that was judged maybe to be risky to the study subjects.

And then you have the stimulant drugs like methylphenidate, ritalin, or amphetamine of different kinds. And then you have things like niacin, which just causes a flush and there’s probably others. But no matter which one you pick, it’s not really going to be fully effective. So it raises the question of “should some research be done at a high level of sophistication that would show that an active placebo is not even possible.” That maybe we have to rethink how this research is done, where we don’t put all the eggs in the basket of a placebo arm. Or that we just do what MAPS did, which is use an inert placebo. But then accept that as the cost of doing business in this field, which is different than other fields of drug research.

Certainly there were a lot of questions about blinding in the study. As we reported, MAPS rejected the lower dose MDMA as an option because they felt it could create anxiety and skew the data. What might researchers consider going forward?

So if Lykos could really partner with the Veterans Administration, really partner with the National Institute of Mental Health, partner with the people in Congress who are very interested in seeing this treatment being available to veterans, this might create a more solid public advocacy system. I also wonder if that more solid system was there, that there could be special access sooner. 

Within the umbrella of the study, there could be practitioners that could be allowed to use the MDMA. Like outside of the formal study, but in a kind of a special access group that would be an observational study. Then that’s a way that MDMA could get to some of the people with trauma, the veterans. Maybe if the veterans group is sponsoring it.

If the National Institute of Mental Health were sponsoring it, it could go to a wider community. Maybe at more academic medical centers that serve veterans, low income and stressed populations. Somehow it could get out there before five years passes and this great Phase 3 study is done. But by then perhaps the FDA has changed their mind again about what they want to approve or not approve. 

I’ve been just thinking about what might lead to the best, to the widest good for the widest number of people with MDMA. And also to do these studies properly. Which active placebo is the best placebo, maybe there needs to be multiple arms to the study where there’s an active placebo, which is a smaller dose. There’s an active placebo, which is an amphetamine or a stimulant or modafinil, which is another stimulant, but that gets very expensive for a private company to do. And that would be a natural thing for the National Institutes of Health to really do.

And maybe by doing those studies, they’ll find out that it’s impossible to create an effective active placebo for such a strong drug that has created such a strong experience as MDMA, or any psychedelic.