Could LSD change the game in anxiety treatment?

A once-controversial psychedelic substance could potentially be a promising treatment for generalized anxiety disorder (GAD). That’s the view of Dr. Rakesh Jain, a psychiatrist with extensive experience in clinical practice, research, and education, affiliated with Texas Tech University School of Medicine. Jain expressed optimism in LSD-based therapy while acknowledging the challenges inherent in such a radical shift, in a recent MindMed analyst briefing on the heels of its MM-120 winning a breakthrough designation for an LSD-based treatment for GAD, based on promising topline data from a phase 2b study.

A once-controversial psychedelic substance could hold the key to treating Generalized Anxiety Disorder (GAD). This is the view of Dr. Rakesh Jain, a prominent psychiatrist who serves as a clinical professor at the Department of Psychiatry at Texas Tech University School of Medicine. While acknowledging the potential challenges, Jain sees significant promise in LSD-based therapies.

The bleak reality of current GAD treatment

GAD is alarmingly common, and its prevalence is on the rise. “Anxiety disorders have tripled in the past two decades,” Jain underscores, “underscoring a major challenge.”

Complicating matters, available treatments are often inadequate for patients. SSRIs like escitalopram and paroxetine are common first-line treatments, while benzodiazepines provide fast-acting relief but are habit-forming so are only used short-term in limited circumstances. Jain highlights a concerning gap in innovation: “The last medication specifically approved for GAD was [duloxetine (Cymbalta)] all the way in February of 2007. That’s simply too long for a disorder that is so prevalent.” He described current medications as slow-acting, limited in effectiveness, and sometimes burdened with debilitating side effects.

GAD is a chronic and progressive disorder. Once it takes root, it’s unlikely to resolve on its own and often worsens over time. “In fact, it often worsens with time and often precedes additional psychiatric disorders,” Jain said.

GAD can have far-reaching consequences. “These individuals know they’re anxious, their brain, body, that mind, everything is negatively affected,” he states. He emphasizes that GAD isn’t just mental: “There’s simply no doubt it’s a disorder that affects both the mind and the body — irritability, muscle tension, sleep difficulties, restlessness, fatigue, difficulty concentrating. It’s quite a laundry list.”

Beyond the immediate suffering, GAD has serious long-term consequences. Jain explains that its severity correlates with “a negative impact on almost every measure of health.” Patients experience “an acute deficit of well-being, a deficit in physical functioning, a deficit in quality of life, and sadly, the presence of significant disability.” He underscores, “It’s not just that they suffer from an anxiety disorder, they actually have an acute deficit of well-being.”

LSD’s potential in GAD treatment

From the 1950s to the early 1960s, LSD was the subject of extensive research, with more than 1,000 scientific articles exploring its potential in treating conditions ranging from alcoholism to neurosis. While this research ground to a halt by the mid-1960s, a renewed wave of rigorous scientific investigation is now underway.

Now, the psychedelic therapies are being explored in a rigorous scientific setting. MindMed’s recent Phase 2b MMED008 clinical trial, the largest well-controlled LSD trial conducted in the U.S. to date, yielded promising results for GAD:

• Participants experienced significant reductions in anxiety as early as two days after a single dose of MM-120. This stands in stark contrast to SSRIs used in GAD settings, which often take weeks to show noticeable effects and have a significant failure rate.
• The positive effects of MM-120 persisted for 12 weeks after a single dose (four week data shown above), indicating the potential for long-lasting relief.
• The improvement wasn’t just statistically significant, but substantial enough for participants to move an average of two categories on a clinical severity scale, from “markedly ill” to the less severe “borderline ill.”
• These results were achieved without any accompanying psychotherapy.

Acknowledging challenges…and reasons for optimism

Jain acknowledges the significant obstacles in bringing an LSD-based treatment to the forefront. “There are challenges,” he admits. “The first challenge is going to be my community, which hasn’t had a ‘real psychedelic’ as a treatment option for [decades].”

While LSD itself isn’t physically addictive or directly lethal, its potent psychoactive effects can lead to distressing experiences known as “bad trips.” These episodes, which can involve panic, terrifying hallucinations, and impaired judgment, potentially can lead to self-harm or erratic behavior. Concerns over these psychological risks, along with sensationalized media reports and cultural anxieties, played a role in the criminalization of LSD in the 1960s, effectively halting scientific research into its potential for decades.

Less frequent, but arguably more concerning, is hallucinogen persisting perception disorder (HPPD), which The New Yorker categorized a decade ago as a “A trip that doesn’t end.” In HPPD, visual disturbances persist long after the drug’s effects wear off.

However, Jain sees significant reasons for optimism when LSD-based therapies are administered in carefully controlled settings. Recent cultural shifts towards openness regarding psychedelics, coupled with compelling research, could sway his colleagues’ opinions

“MM-120 is a major class of psychedelics that doesn’t just change the mind, but they change the brain that drives the mind,” Jain said. “That is now fairly well established.”

Psychiatrists could warm to psychedelics with rigorous evidence

The phase 2b trial could be persuasive for the medical community, even with the challenges posed by LSD’s history. If phase 3 data is as compelling, Jain is confident that the medical community will adopt LSD as a treatment option for GAD.

There are signs of budding acceptance. A 2023 survey of psychiatrists found a “striking positive shift” in attitudes compared to a similar 2016 survey. Over 80% of 131 respondents now believe psychedelics have potential to treat mental health disorders, up from 42.4% in 2016. Younger psychiatrists were especially open to incorporating psychedelic-assisted therapy into their practice if approved. Similarly,  a 2021 survey of UK psychiatrists found that 77.2% believed there was a role for controlled therapeutic use of psychedelics in society. Additionally, a 2023 study of NHS psychologists and psychotherapists found growing awareness of and openness to psychedelic therapies 

Jain acknowledges the significant groundwork laid by Spravato, an FDA-approved ketamine derivative for treatment-resistant depression. Its success in shifting psychiatric practice away from exclusive reliance on daily medications has paved the way for less frequent dosing models.Jain acknowledges the significant groundwork laid by Spravato, an FDA-approved ketamine derivative for treatment-resistant depression (TRD), which is subject to a REMS (Risk Evaluation and Mitigation Strategy), a program mandated by the FDA to manage known or potential risks of certain medications, positions provider centers well to accommodate similar treatment models.

FDA approval scenario remains uncertain

When asked about the prospects of FDA approval for MM-120, Robert Barrow, MindMed CEO, said “it’s a little premature to say definitively.” The FDA approval timeline will depend on finalizing labeling details, a potential REMS, and specific requirements agreed upon with the FDA, Barrow said. “From a logistical and infrastructure standpoint, we see very little standing in the way.”

Again, the precedent of Spravato could pave the way for adoption in the event of FDA approval. “Many Spravato clinics are already equipped to seamlessly transition to providing treatments like MM-120,” Barrow noted. “This suggests a rapid and scalable rollout if approval is granted.”