Psychedelic therapy: A new approach to mental health

pharmafile | December 10, 2018 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  LSD, MDMA, controlled substances, depression, mental health, pharma, psychotherapy 

In November 2018, a Phase 2 clinical trial found that 76% of patients who underwent MDMA-assisted psychotherapy no longer had PTSD, twelve months after undergoing treatment. Louis Goss looks into the process through which an underground therapy entered FDA approved clinical trials.

On the 24^th of December 1912, German pharmaceutical company Merck of Darmstadt, filed patent 274350. The patent, filed to the German Imperial Patent Office in Berlin, is an unassuming one and refers only to the properties of Merck’s obscure creation. 

Methylsafrylamin, the compound that is now known as MDMA, was first synthesised as a means to an end, rather than with any particular purpose in mind. Developed as a precursor to the clotting agent hydrastinine, the chemical was manufactured and patented as part of an effort to avoid existing patents on the synthesis of competitor Bayer’s haemostatic drug. After a standard procedure patent was filed, the compound was forgotten for a number of years.

It wasn’t until the early 1970s that the drug was rediscovered by American chemist and psycho-pharmacologist Alexander Shulgin. While working at Dow Chemical Company, the senior research scientist responsible for the discovery of the first biodegradable pesticide Zectran came across MDMA.

Shulgin described his initial experiences with the drug, stating: “I found myself able to remain completely clear, completely lucid, I had excellent recall. I had none of the cloudiness of recall that sometimes does come with some of the delusional drugs. None of that was there at all. I found myself being able to think honestly. That’s a strange term because you think of honesty as interaction between two people. But to be able to be honest with yourself and think, ‘Why did I do that? Well, I’ll tell you, I did that because of such and such’, was fantastic. It was an honest answer in an area where we’re so used to denial or to disavowing, or to just hiding our feelings. I felt myself come open.”

Shulgin quickly realised the drug’s potential as an aid to therapy. In the late 1970s the California-based researcher introduced the drug to psychotherapist Leo Zeff. Zeff was seen as a pioneer of ‘psychedelic assisted psychotherapy’ and quickly created a network of thousands of therapists – who saw equal potential in the method – around the world. Shulgin described him as the “Johnny Appleseed of the use of MDMA in psychotherapy.”

At the same time, the drug was becoming increasingly popular amongst those interested in MDMA’s effects for recreational purposes. As described by Shulgin: “Outside of the therapeutic community there was, as there almost always is in these cases, a person or a few people who figured out that they could sell MDMA and make a lot of money… The whole thing came to a crisis in Texas where it was used to such an extent that the authorities became concerned.”  MDMA was made a schedule 1 controlled substance in the United States in 1985. The drug had however been illegal in the UK since 1977.

It was at this point Rick Doblin appeared. In 1986, a year after the drug was made illegal in the United States, Doblin founded the Multidisciplinary Association for Psychedelic Studies (MAPS), an organisation established with the primary intention of promoting MDMA-assisted psychotherapy. Born in 1953, Doblin was introduced to MDMA while studying under Czech psychologist Stanislav Grof, a clinical psychiatrist known for his research into the effects of LSD. Firmly believing in the potential of MDMA as a psychotherapeutic aid, Doblin developed the belief that one could effectively work within the system, in order to achieve change. “I started realizing that you could work with the system. Part of the system is designed to help us fight the system. There’s a lot of good things built into the mainstream,” Doblin said in an interview in 2014.

Winning approval

Since being formed in 1986, MAPS has gone on to achieve significant success in the area of psychedelic research. Following decades of work, the non-profit is now entering Phase 3 trials for the use of MDMA-assisted psychotherapy as a treatment for severe post-traumatic stress disorder (PTSD). As of now, MDMA-assisted pyschotherapy has proved astoundingly successful in treating PTSD. One recent Phase 2 trial found that 76% of patients who underwent MDMA-assisted psychotherapy no longer had PTSD twelve months after undergoing treatment. However the process through which these trials were achieved has been long and convoluted. The main obstacle in this process has come from regulatory bodies.

MAPS’ Director of Strategic Communications, Brad Burge, explained: “We were founded in 1986, so we’ve been working for more than 32 years so far. From 1986 to the mid-1990s there were no clinical trials. It was impossible to do any sort of clinical trials with psychedelics, because when proposals were submitted to American regulators, the proposals would disappear, or never come back. They‘d just find themselves in a waste bin somewhere.”

The situation began to change around 10 years after MAPS was formed: “It wasn’t until there were some shifts in the US Food and Drug Administration (FDA) in the late 1990s – during which period they became more accepting of proposals for psychedelic research – that MAPS started our first MDMA-assisted psychotherapy clinical trial in 2000, and that was in Spain. At first we were working with regulators outside of the United States. Switzerland and Spain were our first locations.”

Switzerland, the country in which Novartis subsidiary Sandoz first synthesised LSD, was an obvious choice. “Switzerland has always been very open to psychedelic research. Of course, it’s a very small country with a small regulatory system, so we were actually able to conduct our first LSD-assisted psychotherapy study in Switzerland.”

In contrast MAPS’ Spanish trials did not go so well: “the regulators were prepared to approve it in 2000, but very soon thereafter, it became apparent that culturally Spain wasn’t quite ready. The Madrid anti-drug authority shut down the study before we were able to treat any subjects… it was still too controversial for some of the Spanish regulators.”

Ten years later, MAPS’ was given the go-ahead to conduct their first clinical trial in the United States. “It still took until 2010 for our first Phase 2 trial to be approved in South Carolina. It still took a lot of working with the FDA, working with ethics boards, and also working with the DEA, which governs all of the scheduled drugs in the United States, to actually get approval for that first study. So it still took many years of back and forth, and deciding what the FDA would want so far as double blinds, etc. On top of this we were looking for investigators who were willing to do research with psychedelics, with the expertise, and obviously an actual study site in which it could be conducted, able to get schedule 1 licenses, so there’s all of this regulatory difficulty involved.”

Designing a clinical trial

Having received permission from US regulatory bodies, MAPS was now faced with the challenge of designing a clinical trial. As expanded upon by Burge: “What’s fairly unique about psychedelic therapy research is that we’re not just evaluating a drug, we’re evaluating a drug plus psychotherapy. So the placebo for these trials is either zero milligrams of MDMA, or a low dose of MDMA, plus psychotherapy. The treatment is the full dose plus psychotherapy. Either way, we’re evaluating psychotherapy.” Previously MAPS had found: “some effectiveness with psychotherapy alone, that’s actually fairly strong effectiveness if you compare it to antidepressants or other treatments for PTSD. But then when you add the MDMA to the psychotherapy, we see the effectiveness of that psychotherapy skyrocket. So the hard part has been deciding, how do we conduct ‘psychotherapy trials’?”

As such, it was decided that the psychotherapy itself would have to be standardised in order to conduct a clinical trial: “the way we have done it, and the way the FDA has supported us in doing it, is by having a manualised form of psychotherapy. It’s not just random psychotherapy; it’s actually a booklet that’s published online. It’s available for download. Anyone can see it! It’s essentially a way for us to ensure that participants in the trials are getting the same psychotherapy, or as close to the same psychotherapy as we can give them, between participants.”

“We wanted to ensure that across the different teams, the difference isn’t between the teams and the psychotherapies they’re administering, but the difference is between, well obviously it’s a double blind trial! This manualised form, we evaluate it through video recordings, we record videos of all of the psychotherapy sessions and then we have teams of independent adherence raters that go through all of the videos, and moment by moment evaluate it, where it accords with this psychotherapeutic method that we’ve developed. Essentially we were making sure that the therapists are actually delivering the treatment in the way that others are doing also.”

The placebo effect

In 2008, a meta-analysis conducted by Harvard psychologist Irving Kirsch, found that 82% of the response to antidepressants could be accounted for by the placebo effect. While the meta-analysis itself is mired in controversy, the paper demonstrates the challenges associated with studying treatments for mental health conditions, particularly when it comes to the placebo effect.

“The placebo effect has been one of the biggest challenges in conducting our research,” Burge said. “Mainly because it tends to be fairly obvious as to when someone’s ingested MDMA.” The issue is further complicated due to the fact that many of the therapists who administer MDMA-assisted psychotherapy, themselves undergo “an active MDMA-assisted psychotherapy session,” as part of an ongoing MAPS-sponsored Phase 1 safety study in healthy volunteers, through which therapists are entered on a voluntary basis. Burge explained that “There’s not necessarily science to suggest that this is necessary but it certainly stands to reason, and the FDA supports this rational, that having some kind of internal experience is helpful.” As such: “it tends to be fairly obvious as to when someone’s ingested MDMA. Especially to those with some experience with it and therapists obviously have experiences with it”

“So figuring out how we were going to do the double blind was tricky. We still managed to fool most participants and therapists fairly often. Probably about half the time, or maybe a little less than half the time, they’re not sure which dose. Instead of using zero milligrams we primarily used active placebos. Rather than a straight placebo with zero milligrams of MDMA, we used active dose placebos; essentially that means just a very small dose of MDMA compared to a larger dose of MDMA. In our most recent study, that was 40 milligrams, compared to 100 or 125 milligrams. The theory is that by causing some small MDMA effects we can confuse the participants and therapists as to which dose they got. That has been fairly effective.”

However, Burge noted: “Ultimately it seems that the FDA isn’t super concerned with double blind, and that doesn’t just to apply to psychedelic research. What they’re trying to see is safety and effectiveness. Our overall Phase 2 results found that about 25% of those who received the placebo treatment, which is either zero milligrams of MDMA or the low dose MDMA, plus psychotherapy did not have PTSD anymore. That’s still quite astounding – 25% is about a typical placebo result and it’s also about what the effectiveness of SSRI’s is!”

Set and setting

The term ‘set and setting’ was first used by Harvard University psychologist and LSD pioneer Timothy Leary, in describing the context in which one undertakes a psychedelic experience. The phrase, along with “turn on, tune in, drop out”, achieved widespread recognition, and in some circles, notoriety, during the countercultural era of the 1960s.

While set refers to the ‘mindset’ of the individual going into the psychedelic experience; setting refers to the environment and cultural context within which a person undertakes the psychedelic ‘trip’. Both ‘set and setting’ can have a profound effect upon the way through which one experiences the effects of a psychedelic drug. As such, in conducting a clinical trial for a psychedelic assisted course of psychotherapy, ‘set and setting’ must be taken into account.

In many ways, issues surrounding ‘set and setting’ have plagued psychology and the social sciences in recent years. The question came to the forefront in a paper titled “The weirdest people in the world?” which claimed that “Behavioural scientists routinely publish broad claims about human psychology and behaviour in the world’s top journals based on samples drawn entirely from Western, Educated, Industrialized, Rich, and Democratic (WEIRD) societies.” This in turn leads to a skewed perspective in which empirical claims are made on the grounds that they are true for a WEIRD subset of individuals.

MAPS sought to circumvent this bias in a number of ways. As explained by Burge: “As far as personal background, spiritual beliefs, or ethnic and cultural backgrounds, we have been doing studies in various locations. That’s how we are making sure that belief systems, and even languages, work the same or similarly. As of now, we’ve completed one Phase 2 trial in Switzerland and one in Israel. Those were in Swiss German and Hebrew, and we were also able to see positive results. And so the language doesn’t seem to matter. Nor do religious or spiritual beliefs.”

“Nor does the source of the PTSD seem to matter, whether they’re a military veteran, or have PTSD from sexual assault or a lightning strike – it all seems to work about the same. Our upcoming Phase 3 trials trial will be through the FDA and through that we’ll have data from Canada, the US and Israel. All of that data will be looked at by the FDA. We’re also starting trials in Europe with the European Medicines Agency (EMA) next year.”

However Burge noted that the majority of participants shared some similarities in that they were likely to be familiar with psychotherapy: “The people who we’ve enrolled in the Phase 2 trials have all had chronic PTSD and several of those participants in Phase 2 trials have also had chronic and treatment resistant PTSD. So all of the people who’ve been in the trial so far have had PTSD for a number of years and have tried other treatments including medications and/or psychotherapy. As such, all of the people coming into this trial have experience with other treatments, and a lot of them have experiences with psychotherapy.”

Real world data

The unconventional nature of the treatment, and the illegality of MDMA itself, meant that the process through which MDMA-assisted psychotherapy entered clinical trials differed greatly from the conventional process through which the majority of pharmaceutical drugs enter major studies. As described above, knowledge and appreciation of MDMA-assisted psychotherapy was spread through relatively small networks of particularly open-minded and foreword-thinking psychotherapists, who had for the most part seen potential in the treatment as individuals. Above all, this led to a reliance on ‘real world evidence’ and anecdotal reports.

As explained by Burge, the model through which the drug came to be understood, mirrored that of hallucinogenic drug LSD: “In the 1950s and 1960s, even as far back as the 1940s, there were thousands of case reports published about the use of LSD and other psychedelics in therapy, and they were published as articles in magazines and newspapers or peer reviewed journals or just little periodicals.”

However twenty years later, researchers found themselves in a similar position with a yet to be criminalised MDMA:  “There were many, many case reports of people using MDMA in psychotherapy for PTSD, before it was even criminalised in the 1970s and early 1980s, and we were able to use that, plus the basic safety studies to justify approving the Phase 2 and later the Phase 3 trials. Those case studies were absolutely crucial… That was how we got approval for the PTSD studies as well. That evidence combined with preliminary evidence about MDMA’s safety in a clinical setting – we have ample evidence of that, MDMA has already been shown to be safe enough in moderate doses, a moderate number of times, in therapy. That’s why we’re able to do Phase 3 clinical trials.”

Although the original process through which this data was collected saw a relatively small network of researchers and psychotherapists collect disparate pieces of anecdotal evidence from an array of journals and print publications; another form of network soon took over in transforming this previously drawn out process into a huge and fast moving operation. As said by Burge “Now we have the internet and that dramatically facilitated the gathering of case reports. You can just post on a message board and within a few months you can have hundreds or even thousands of people saying ‘oh yeah this has been helpful’ or ‘this hasn’t been helpful’, or ‘this had this effect or that effect’ and the challenge is doing something with all this data.”

The effectiveness of this approach was demonstrated by clinical psychologist Alicia Danforth who sought to explore the potential of MDMA-assisted psychotherapy as a treatment for social anxiety in autistic adults. Danforth was initially inspired by anecdotal reports. “In the case of social anxiety in autism research, that was the basis.” Burge said. “Alicia Danforth’s dissertation research was surveys and interviews about people who have tried MDMA or ecstasy and found some sort of benefit.” 

Money, money, money

Since the ‘golden era’ of SSRI’s, there has been a 70% drop in the number of research programmes looking into drugs for mental health conditions. Meanwhile, the pharmaceutical industry has largely held back from investing into research into new psychopharmacological drugs in recent years. The area of mental health still suffers from chronic underinvestment. This overall lack of funding was epitomised by the findings of the UK Health Research Analysis 2014 report, which revealed that just 5.8% of the health research budget is spent on mental health research. This represents just £9.75 per person for each person living with a mental health condition, 150 times less than the amount spent on those with cancer.

This lack of investment is especially apparent in the case of psychedelic-assisted psychotherapy. As noted by Burge: “You can’t patent psychotherapy and you can’t patent MDMA. For that reason there’s been little investment… The reason MAPS decided to do it in a non-profit way is due to the fact that at the time we started, and probably now today, there’s just not enough investment. There’s not enough promise of return. Instead we’ve taken donations and the benefit of donations is we don’t have to pay them back. So in collecting donations that’s what’s enabled us to get to this point.”

However, research into psychedelic assisted psychotherapy is beginning to take hold. Compass Pathways, a London-based biotech, whose “first major initiative is developing psilocybin therapy through late-stage clinical trials in Europe and North America for patients with treatment-resistant depression,” was founded in 2016. The company is now initiating Phase 2b trials into the effectiveness of ‘magic mushroom’ ingredient psilocybin as a treatment for treatment-resistant depression. 

Burge commented: “MAPS’ research was able to decrease the cultural stigma surrounding psychedelic-assisted psychotherapy and that is what has enabled Compass Pathways to exist. Now they’re at a point where they see a way to move psilocybin through the FDA, and later the EMA approval process, and potentially be able to recoup some of that investment for their investors. So it’s really just a different way of gaining the resources to move these drugs through the regulatory system.” 

Nevertheless, Burge sought to make clear that “[MAPS] are just developing another drug treatment for a psychiatric condition. It’s important to emphasise that this is a treatment that people only go through on a small handful of occasions – so three to five sessions of MDMA-assisted psychotherapy. People don’t take the drug every day. Even when it’s approved it won’t be a take home drug. People won’t go to the pharmacy and pick up a bottle and go home with it. It’s always going to be a very limited number of times, in a supervised therapeutic setting. That’s an important thing to highlight because when people see the headlines they think ‘MDMA, it’s just another drug!’ But it’s really just a short period of treatment compared to daily pharmaceuticals. It’s a major thing to highlight.”

However Burge concluded in noting the continuous nature of MAPS’ work. “Last but not least, in order to conduct the Phase 3 trials in Europe – in order to make MDMA assisted psychotherapy legally available through the EMA – we need to raise another $10 million dollars. We’ve already raised $26.7 million for the FDA trial, so it’s not completely impossible, but there is some work that we have ahead of us.” And for those interested, he added: “We’re planning to have at least one of the phase 3 sites in the UK.”

Louis Goss