Can LSD break the 20-year drought in anxiety treatment?

In August 2024, MDMA, which is better known as ecstasy, faced a setback as a potential therapy for PTSD—a complete response letter from the FDA. While its developer, Lykos Therapeutics, plans on launching a new Phase 3 trial with tighter scrutiny, another psychedelic company, MindMed, is readying a pivotal study of LSD for generalized anxiety disorder, another condition with scant and often negligibly effective treatment options.

Giving a stagnant anxiety treatment landscape a push

“There has been little pharmaceutical innovation in anxiety treatment for decades,” says MindMed CEO Robert Barrow. SSRIs and SNRIs remain the first-line pharmacological treatments while benzodiazepines have faded somewhat owing to addiction worries. “The last FDA approval for anxiety was Cymbalta,” he said. While its original approval was for depression in 2004, the drug won an indication for Generalized Anxiety Disorder (GAD) in 2007. “That’s 20 years without a meaningful new drug in anxiety.”

The need for innovation is stark. Anxiety and depression disorders have “some of the highest impact on morbidity and general well-being,” Barrow said. A 2023 JAMA investigation found that patients with depression or anxiety had a roughly 40% higher long-term mortality rate than those without similar conditions. While new SSRIs have been developed, many patients remain untreated or undertreated. “We’ve seen virtually no innovation in either field, especially in anxiety,” Barrow noted. “The trajectory for these disorders has continued and even accelerated.”

Enter MM-120, MindMed’s lysergide d-tartrate—a pharmacologically optimized form of LSD that received FDA Breakthrough Therapy Designation in March 2024. The company’s Phase 2b results showed promising outcomes: a 65% clinical response rate and a 48% remission rate in GAD patients, sustained over 12 weeks.

Reimagining the patient experience

After Albert Hofmann discovered LSD’s psychedelic properties in 1943, the compound became the subject of extensive scientific inquiry, generating more than 1,000 research papers by mid-century. This promising trajectory was disrupted when advocacy for recreational use, particularly by Timothy Leary and Richard Alpert at Harvard, shifted public perception. As media coverage transformed from scientific interest to sensationalist stories, states began criminalizing LSD in 1966. By 1970, under Nixon’s Comprehensive Drug Abuse Prevention and Control Act, it was classified as Schedule I—effectively halting legitimate research.

In one way, MindMed aims to restore the therapy to its former status as a drug with particular clinical promises for mood disorders. The company envisions a treatment model similar to Spravato, Johnson & Johnson’s esketamine nasal spray for depression, but with potentially fewer restrictions. “It needs to be a monitored setting with appropriately trained providers, but not necessarily a medical setting where they need to take blood pressure and heart rate readings,” Barrow explains.

While a ketamine experience typically lasts from thirty minutes to two hours, LSD experiences are longer-lived, lasting anywhere from 8 to 12 hours. This duration requires special considerations for patient comfort, but MindMed sees this as manageable within existing clinical infrastructure. “Per FDA guidance, patients are kept under observation by two people throughout the day,” Barrow said. “We envision something similar to Spravato, but with less monitoring burden since we don’t see the physiological risks that Spravato has.”

Plans to tap new clinical infrastructure

The company aims to tap into the growing network of interventional psychiatry clinics, which have expanded significantly since the introduction of ketamine treatment. Regarding the room setup and patient management, Barrow notes, “We’re not overly prescriptive about the room. It needs to be a comfortable setting in interventional psychiatry clinics. These clinics typically look like what you’d expect from a psychotherapy office. A living room vibe is a reasonable description—it should be a comfortable setting since someone’s going to be there for the day.”

The approach represents a significant shift from earlier psychedelic therapy models that emphasized the role of specialized therapists. MindMed has focused instead on what Barrow calls “drug-only” administration, a decision that seemed risky three years ago but has since been validated as the field has evolved.

Redefining success

This streamlined approach could make the treatment more accessible to the millions suffering from anxiety disorders, aligning with Barrow’s vision: “When we get these drugs out in the world, success doesn’t look like treating 10,000 people. Success looks like meaningfully impacting those 20-30 million people, and that cannot be done if artificial barriers are put in place.”

Other developers, such as Compass Pathways and Cybin, have made similar moves, focusing more on the drug itself rather than combining it with in-depth psychotherapy. “We want to provide the highest quality data in the most thoughtful program, and answer these questions beyond a doubt,” Barrow said. “It requires an intentional balance between ensuring safety, holding ourselves to the highest degree of rigor and quality, while not artificially constraining things.” MindMed’s focus on rigorous clinical trial design addresses concerns about functional unblinding and placebo effects. “Our Phase 2 results informed the selection of the 100 microgram dose level.

Given the unique challenges with developing psychedelics—the acute perceptual effects, the reality that almost everyone knows when they’re getting an active dose—we’ve taken a complementary approach,” Barrow explains. Embarking on Phase 3 trials with LSD is a landmark achievement. “It’ll be the first Phase 3 ever conducted with LSD,” Barrow confirms. “This drug is unique in terms of activity, clinical promise, and attractiveness for delivery sites and patients. The magnitude and durability we see is unmatched.”

The first Phase 3 LSD trial

MindMed’s Phase 3 program will begin by year-end, with two pivotal trials in GAD totaling 440 patients. The company is also planning a registrational study in major depressive disorder for early 2025. Initial results are expected by the end of 2026. If successful, it would mark the first-ever FDA approval of LSD for any indication.

If LSD can win FDA approval for conditions such as depression and anxiety — which can have significant symptom overlap — it would be fitting as LSD itself helped researchers better understand the role of serotonin in the brain in the 1950s. The scientific understanding of serotonin’s role in mental health grew substantially from this point forward. That improved understanding of serotonin would lead to the development of the following decades. “The brain is a very complex organ we don’t fully understand,” Barrow reflects. “We embrace broader pharmacology—drugs like MM-120 LSD that hit multiple receptors and have known functional activity. This could be the key to meaningful change in novel treatments for these disorders, both in autism and neurotic illnesses like anxiety and depression. We’re really excited about the potential from what we know about these drugs.”

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Filed Under: Psychiatric/psychotropic drugs, Regulatory affairs
Tagged With: anxiety drug development, breakthrough therapy designation, lysergide clinical trials, mindmed MM-120, psychedelic therapy GAD
 

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