This story is part two in a two-part series looking at the psychedelics drug development landscape. Part one, which looks at investors' interested in psychedelics, is available here.
Psychedelic drugs are coming out of the jungle and creeping closer to the market, but developers will have to overcome a kitchen sink of regulatory issues—or, maybe more accurately, a living room couch?
Unlike modern pharmaceuticals, such as antidepressant pills or cancer-fighting infusions, the medicines used in psychedelics-assisted therapy are not standalone treatments. Instead, these drugs help a patient “reset” their brain as they work with a psychotherapist to overcome ailments such as depression and addiction.
“The FDA was unsure what to do with the therapy part of it. Do they look at the therapy training program? What is the label going to say? How much do you put in the REMS [Risk Evaluation and Mitigation Strategy] and how much do you put in the label?” said Amy Emerson, CEO of MAPS Public Benefit Corporation, a subsidiary set up by the nonprofit Multidisciplinary Association for Psychedelic Studies to develop and commercialize its MDMA-assisted treatment for post-traumatic stress disorder (PTSD).
Psychedelics treatment developers also must overcome intellectual property challenges, because these drugs are in the public domain or have been used by Indigenous peoples for millennia. They have to figure out how to open up access to all who need treatment. And they may need to create new business models to develop these treatments, not only to help patients and turn a profit but also to do it ethically.
A blunt tool
Numerous studies have shown the promise of psychedelics, such as LSD and psilocybin, but research in the field has been hindered by federal law. The Controlled Substances Act of 1970 classified psychedelics as Schedule I drugs with “no currently accepted medical use.”
But the tide is turning, thanks in part to the shortcomings of traditional mental health care. Current treatments don’t always work well, and they carry side effects such as an increase in alcohol cravings or an increased risk of suicide.
Research and investor interest in psychedelics-based treatment has rebounded in the last decade. Privately funded research centers have popped up at prestigious institutions like Johns Hopkins University and the University of California, Berkeley.
“We have very blunt tools that are mostly focused on symptom management rather than trying to help people with their own resiliency and internal ability to make change and potentially overcome the challenges they are having in life,” said Evan Wood, M.D., Ph.D., chief medical officer at Numinus, which has partnered with MAPS and Syreon on clinical trials of MDMA- and psilocybin-based therapy, respectively.
The hope is that psychedelics added to talk therapy can achieve what previous approaches haven't, especially as the COVID-19 pandemic has exacerbated mental health problems and highlighted the need for better options, said Jeeshan Chowdhury, M.D., Ph.D., CEO of Journey Colab, a biotech working on a synthetic form of mescaline, a hallucinogenic compound found in some species of cactus, to treat alcohol use disorder.
For MAPS, the stigma around psychedelics did the nonprofit no favors as it tried to get human trials off the ground in the 1990s.
Because of a wealth of research into the potential harms of MDMA, the nonprofit didn’t need to run a phase 1 study to figure out the best dose of the drug or its side effects.
The nonprofit started its first phase 2 trial in 2004, nine years after it completed the required preclinical studies in 1995.
“We had a hard time getting the first study approved because politics were being put in front of the science,” Emerson said. Another barrier was money—MAPS is funded by philanthropy, rather than deep-pocketed venture capitalists like many a psychedelics-focused biotech today. Instead of going full speed ahead on multiple phase 2 trials, MAPS had to carry them out slowly and sequentially, Emerson said.
The nonprofit moved into phase 3 in 2018 and is now recruiting patients for a second phase 3 trial. An FDA decision is anticipated in 2023.
Though psychedelics research has certain requirements that other drug R&D doesn’t, such as secure drug storage and monitoring patients overnight, Emerson views MAPS’ work as no different from other treatments that are among the first of their kind.
A traditional setting
MAPS’ therapy harnesses MDMA, also known as ecstasy or molly, which was first synthesized by German pharma Merck KGaA in 1912. But other psychedelics-assisted therapies are based on compounds such as psilocybin, mescaline and N,N-dimethyltryptamine, which are found in nature and have been used by Indigenous populations for millennia.
That’s why Chowdhury of Journey Colab thinks of the company’s work as “translating therapies from a traditional setting to a clinical setting” rather than simply “drug development.”
Some patients may have the means to travel to Indigenous communities to benefit from such treatments, but “there are some issues there in terms of sustainability, extractive models and impact on those communities,” Chowdhury said.
Some of the plant sources for these medicines are endangered, for example, while history is rife with examples of colonizers exploiting Indigenous peoples, their expertise and their lands.
“We need to meet patients and families who suffer from alcohol use disorder where they are … We need to bring these therapies to people in their homes—not everyone can or should go to the jungle to experience these therapies,” Chowdhury added.
Translating these therapies into a modern healthcare context includes developing synthetic versions and creating methods to deliver reliable, consistent and measurable doses to patients.
“For some traditional psychedelic therapies, the 'method of administration’ is smoking, which is not appropriate for a clinical setting,” Chowdhury said. “A patient in the clinic versus in a ceremony is going to receive a different type of therapy.”
These inventions could address the issue of intellectual property, where companies would patent delivery methods and treatment protocols rather than the psychedelics themselves, some of which are in the public domain and cannot be patented. Johnson & Johnson did just that with the hallucinogenic “party drug” ketamine by creating a new formulation called esketamine, which was approved in 2019 as the nasal spray antidepressant Spravato.
Atai Life Sciences is working on shorter-acting psychedelics, which could lessen treatment time for patients and potentially deliver the benefits of psychedelics without their hallucinogenic effects.
Still, psychedelics developers remain vulnerable to competitors that could undercut them with cheaper versions.
That’s a concern for Compass Pathways, a biotech working on psilocybin-based therapy for treatment-resistant depression. The company noted competition as a risk in a recent securities filing, not just from biotech and pharma companies but also from nonprofits including the Wisconsin-based Usona Institute, which is researching psilocybin-based therapy for major depressive disorder.
To encourage psychedelics R&D, Numinus’ Wood thinks this class of therapies shouldn’t be lumped in with modern pharmaceuticals and instead needs its own regulatory pathway.
“This is not a pharmaceutical drug—a cancer drug, chemotherapy drug or new heart disease drug—but a naturally occurring molecule people have been using for hundreds if not thousands of years,” Wood said. “There probably needs to be a different regulatory regime for it.”
MAPS tried to model its MDMA-assisted psychotherapy after traditional regulatory processes for other pharmaceutical drug approvals.
“I wanted to make it look exactly how the FDA or any regulator would expect any other study and drug development program to look,” said Emerson, who started out with MAPS as a pro bono consultant in 2003 and became the CEO of its Public Benefit Corporation in 2014.
A new business model
Some players believe the field needs a new business model to develop and market the therapies. Others think current models can be tweaked, seeing as companies like J&J, GW Pharma and Jazz Pharma have brought versions of Schedule I drugs to market as new medicines for depression, epilepsy and narcolepsy.
Srinivas Rao, M.D., Ph.D., chief scientific officer of psychedelics treatment maker Atai, said in the case of Spravato, patients can self-administer the drug but have to do so under the supervision of a healthcare provider in a certified Spravato treatment center over several weeks.
“Was that a markedly different business model? I’d argue no,” Rao said. "If we can bring it down to make [dosing] much less frequent, we’ll be in pretty good shape.”
But Emerson and Chowdhury think this type of treatment requires a bigger change.
“We can’t just take existing company structures and plug them into psychedelics—the opportunity with this class of compounds is it forces us to think about different structures, different ways of approaching mental health,” Chowdhury said.
For MAPS, a nonprofit dedicated to research, that meant setting up a public benefit corporation rather than a traditional for-profit structure. This allowed them price the drug to maximize patient access while also funding future research.
Journey is treading somewhere between nonprofit and for-profit by putting 10% of its founding equity into a trust to share profits with employees, the therapists and caregivers who will administer the treatments, and the Indigenous communities to which the company’s medicines trace their roots.
A comfortable couch
As MAPS’ PTSD treatment and other psychedelics-based therapies inch closer to regulatory review, the next big question will be how to translate treatments from a tightly controlled clinical trial environment to the real world.
“The setting [of therapy] is very important. This is something we have guidelines around and we would have guidelines post-approval as well,” Emerson said. “It should be comfortable, more like a living room setting than a hospital room.”
That includes music, eye shades and a comfortable couch, but the rooms could look different depending on who is providing treatment, ranging from a community-based private practice to clinics at an institution, she said.
MAPS is gaining experience in the real world through an Expanded Access Program, which is approved to treat 50 people.
For now, the MDMA-based treatment will always be given in a clinic under the eye of a therapist. But looking down the road—and if the data support this—patients may be able to take the treatment at home after a certain number of sessions in the clinic, or a therapist may administer treatment in a patient’s home. Rao of Atai envisions a general practitioner offering these treatments in their offices but acknowledged this would be “a long way off.”
“We have to be negotiating really hard with payers to not only cover the drug but to have new codes to cover the therapy,” Emerson said. “Therapy is more expensive than the drug. Therapy is not something we get to set the price for—we can’t do that, it doesn’t belong to us.”
But companies don’t need to start from scratch: They can build on existing structures, like the 16,000 rehabilitation centers in the U.S., the millions of people already going to therapy each week, and insurance codes and reimbursement models to make this work for patients, Chowdhury said.
“There are questions about how we’re going to pay for this, build all this,” Chowdhury said. “Already, we are paying for it, especially in addictions. The amount we spend on frustratingly unsuccessful therapies is enormous."