Depression Is Notoriously Difficult to Treat. Can Psychedelic Therapies Help?

Psychedelic drug developers are homing in on the potential $16 billion depression treatment market, with a particular focus on treatment-resistant depression.

Pictured: Psychedelic plants in front of blue squiggly lines/Taylor Tieden for BioSpace

A highly heterogeneous disease, depression has long challenged drug developers. While effective treatments exist for some patients, many are still left behind by current regimens. Now, with the global depression treatment market projected to top $16 billion by 2027, psychedelic drug developers have their sights set on the space, with six programs currently in clinical development, according to Psychedelic Alpha.

The current standard of care for depression comprises selective serotonin reuptake inhibitors (SSRIs) such as Eli Lilly’s Prozac and Pfizer’s Zoloft, along with depression-focused psychotherapy. However, at least 30 percent of people with major depressive disorder fail to respond to two or more antidepressants, a condition called treatment-resistant depression (TRD). Less than 15% of patients with TRD reach remission with the standard of care, according to Theis Terwey, CEO and co-founder of GH Research, which is developing the psychedelic drug 5-MeO-DMT for the treatment of TRD.

There is precedent for using psychedelics to treat TRD. Johnson & Johnson won approval for Spravato (esketamine) for TRD in 2019, though the company does not consider the nasal spray to be a classic psychedelic. Carlene MacMillan, an interventional psychiatrist and chief medical officer at the mental health treatment and research technology platform Osmind, explained that Spravato is not a classic psychedelic because it does not cause a hallucinatory effect and because of how it acts in the brain. In clinical trials, patients who received Spravato saw “superior” and “sustained” improvement in their depression symptoms compared to those who received a placebo and an oral antidepressant, according to J&J.

Companies like GH and Compass Pathways are now seeking to improve on those results with 5-MeO-DMT and psilocybin—with the hallucinogenic qualities intact. There are currently no other psychedelic drugs on the market, though MDMA, being developed by Lykos Therapeutics for post-traumatic stress disorder (PTSD) and up for FDA approval in August, could set the stage for more psychedelic-based treatments for mental health.

In depression, in particular, psychedelics stand to offer something new, MacMillan told BioSpace. “Most of the medications that we have on the market, and have had on the market for several decades, are all just variants of kind of the same thing, acting on serotonin in some way, taking weeks to months to work,” she said. The potential for psychedelics to treat TRD in a much more rapid way is “really very, very high.”

Psilocybin Leads the Way in Compass’ Phase III for TRD

London–based Compass is in Phase III TRD trials with psilocybin, a serotonin receptor agonist that occurs naturally in some mushroom species.

Psilocybin binds to the 5-HT2A receptor for serotonin, explained Guy Goodwin, chief medical officer at Compass, provoking “a series of downstream changes.” While he acknowledged that researchers don’t know which of these changes is functional, he said a change in connectivity is seen on the MRIs of patients treated with psilocybin.

“Normally, at rest, the brain has a number of modules, which seem to prefer to fire together, dotted around the brain, and one of them is sometimes called the default mode network.” When a patient takes psilocybin, “that kind of breaks down, and these strict, kind of separated modules become much more interconnected,” he explained. “It’s sort of as if you have a kind of breaking of the existing strict topography of the brain into something that is much more fluid and much more potentially malleable.” The hypothesis is that the brain is then able to see situations and problems “in a different way.”

MacMillan agreed. “The psychedelics allow you to teach an old dog new tricks.” She said that this can be helpful in treating depression and specifically pointed to psilocybin’s potential. “Psychedelics, particularly psilocybin, have shown great promise at helping people who are not traditionally helped, and faster.”

In Phase IIb trials, Compass’ candidate, COMP360, showed “a highly statistically significant reduction in depressive symptoms after three weeks” following a single 25-mg or 10-mg dose in combination with psychological support, with the response lasting up to 12 weeks, according to COMPASS. The control group received the same therapeutic support together with a 1-mg dose of COMP360. A Phase III trial is underway, with a study completion date of May 2025.

Compass isn’t alone in pursuing psilocybin for the treatment of depression. Braxia Scientific is investigating a psilocybin-assisted therapy in Phase II for TRD.

DMT Close Behind in Phase II from GH Research

Dublin-based GH is developing a novel formulation of 5-MeO-DMT, a psychedelic tryptamine found in several plant species. The candidate, GH001, is currently being studied in a Phase IIb trial for TRD, for which the company expects topline data in the third or fourth quarter of 2024.

5-MeO-DMT was particularly attractive to GH due to its rapid and short-acting nature when inhaled. Terwey said this can address some of commercial feasibility issues inherent in longer-acting compounds like psilocybin and LSD. Such longer-acting drugs often also involve additional visits for psychotherapy or psychological support, he said, adding that this can be challenging to incorporate into an eventual label and commercial model.

5-MeO-DMT represents a pure pharmacological approach, Terway said. As a trial participant, “you’re really present with your ego during the experiment,” he explained. “So it’s not much to process or not really a lot of memories in context of a narrative. It’s more a deep feeling that develops and that we felt could be given without those cumbersome preparation and integration visits.”

MacMillan disagreed, however, saying that the experience with 5-MeO-DMT is “extremely intense” and has a much more significant risk profile than psilocybin, LSD, mescaline and MDMA.

In addition to GH, Beckley Psytech is in Phase IIb trials with a 5-MeO-DMT formulation for TRD. Meanwhile, Biomind Labs and Viridia Life Sciences (atai Life Sciences) are each studying a related compound simply called DMT, which occurs in many plants and animals, including humans, for TRD.

Targeting Difficult-to-Treat Depression

While still investigational, psychedelics could be an effective treatment for those with more difficult-to-treat depression, MacMillan said.

Patients whose depression stems from life circumstances will generally respond better to traditional medicines and traditional psychotherapy than will patients with a genetic predisposition to depression, she noted. Additionally, many patients with TRD have comorbidities “that are making it harder” to treat, she said, highlighting personality disorders like narcissism and obsessive-compulsive disorder.

“Those patterns are not really addressed at all by the traditional antidepressants,” MacMillan said. As psilocybin or MDMA open new ways to learn, “I think it stands to reason that somebody that has a personality disorder and then gets related therapy for that disorder after a psychedelic experience could potentially actually change some of those underlying things as well.”

MacMillan indicated she would be comfortable using certain psychedelic therapies in her practice, providing a strong Risk Evaluation and Mitigation (REMS) program is in place. “As a psychiatrist, I think that we are well positioned to work with patients that have more complex psychiatric concerns.”

While MacMillan expressed optimism about the potential of psychedelics, she noted that other rapid-acting neuromodulation treatments like transcranial magnetic stimulation are also showing promise. “I think it’s important that we see broadly treatments for TRD and not get overly focused on psychedelics being the only way, because it’s just a different time in our field now.”

Heather McKenzie is a senior editor at BioSpace. You can reach her at Also follow her on LinkedIn.