According to the World Health Organization, nearly 1 in 7 people in the world live with a mental disorder. Despite this escalating need, the pharmacological arsenal for treating these conditions has seen limited innovation in recent decades, largely revolving around medications like selective serotonin reuptake inhibitors (SSRIs) that require daily dosing and often come with side effects and variable efficacy.
In this landscape of urgent need and therapeutic stagnation, a surprising class of compounds is undergoing a rigorous scientific reappraisal: classic psychedelics. Once relegated to the fringes of both counterculture and legitimate research following their criminalization in the 1970s, substances like psilocybin (found in “magic mushrooms”), MDMA, and lysergic acid diethylamide (LSD) are now at the heart of a “psychedelic renaissance.” Driven by promising early clinical results, venture capital investment, and a shifting cultural and regulatory environment, researchers are applying modern scientific methodologies to evaluate these drugs as potential breakthrough therapies for conditions including major depressive disorder (MDD), treatment-resistant depression, post-traumatic stress disorder (PTSD), and substance use disorders.
Leading this charge are biopharmaceutical companies dedicated to navigating the complex path from promising compound to approved medicine. One such company is Definium Therapeutics, a late-stage clinical biopharmaceutical firm (formerly MindMed) developing novel treatments for mental health disorders. Definium is currently advancing a pharmaceutical formulation of LSD, known as lysergide tartrate (DT-120), through Phase III clinical trials for Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD). Accompanying this clinical work is their Rerouting Minds campaign, an educational initiative aimed at shifting the conversation around psychedelic medicine from one of stigma to one of science and potential.
To understand the science, the strategy, and the potential future of this emerging paradigm, Drug and Device World spoke with Definium’s chief medical officer, Dr. Dan Karlin. He details the distinctive mechanisms of psychedelic-assisted therapy, the high regulatory bar the company is aiming to meet, and how a successful approval could reshape patient journeys and psychiatric care itself.
From Counterculture to Clinic
The fundamental premise of most current psychiatric medications is symptom suppression through daily administration. Dr. Karlin draws a clear distinction with the psychedelic model. “What we have available are drugs that are taken on a daily basis… They are experienced as symptom suppressive,” he explains. While valuable for many, this approach often manages symptoms rather than addressing underlying patterns, and benefits typically cease when medication is discontinued.
Classic psychedelics like LSD propose a different paradigm: intermittent dosing with the potential for durable effects. “What we know about these drugs is they’re taken once or at some interval… there is a period of transient change that people experience,” says Karlin. The acute effects—lasting several hours—are followed by a post-acute period where, “even though the drug isn’t in the person anymore, the drug’s long gone… there is a persistent change in how that person feels.”
This persistent change, Karlin emphasizes, is often qualitative rather than merely quantitative. “In general, that change isn’t suppressive. They don’t feel less. In general, what they describe is that they feel differently. They feel better in relation to the things that used to cause them anxiety, not better in relation just to the symptom of anxiety.” Neuroscientific research suggests this may relate to the ability of psychedelics to temporarily disrupt rigid patterns of brain network connectivity (like the default mode network, associated with self-referential thought) and increase neuroplasticity, potentially allowing patients to form new cognitive and emotional associations.
Rigorous Trials for a Historic Compound
LSD was first synthesized in 1938 and generated significant psychiatric research interest in the 1950s and 60s. However, as Dr. Karlin notes, that research was conducted under “very different sets of scientific standards.” For Definium, the historical promise provides confidence but not a foundation for regulatory approval. “None of our application with the US Food and Drug Administration (FDA) to get this drug approved would be predicated on that historical research,” Karlin states unequivocally.
The company is therefore executing a full, contemporary drug development program. This includes clinical pharmacology and toxicology studies, and, most critically, a robust late-stage clinical trial portfolio. Karlin outlines a substantial pathway: “We have completed a phase 2B study in generalized anxiety disorder… we have to wrap up two Phase III studies in GAD that we’ve already started… and we have a third Phase III study in MDD… We intend to start a fourth Phase III study.” This level of evidence, he asserts, is the “very high standard” required for any new psychiatric drug approval, deliberately distancing the effort from earlier, less rigorous eras of psychedelic research.
Navigating Stigma with Science and Openness
One of the most significant hurdles for any psychedelic medicine is not just clinical or regulatory, but cultural. LSD carries decades of sociopolitical baggage and stigma. Definium’s approach, as described by Karlin, is one of direct engagement. “We’ve decided as a company across everything that we do to face things head on… not to look away from things that might be important just because they’re complicated.”
The Rerouting Minds campaign is a core part of this strategy. Rather than avoiding LSD’s complex history, the campaign acknowledges it. “No one would believe us if we said that the history of LSD was simple… We have chosen to very purposefully look at that complicated history, not to run from it,” Karlin says. The goal is to meet stakeholders—healthcare professionals, patients, payers—where they are. “Let’s meet people wherever, whatever it is they know… and help them to come toward a view where they understand why we’re doing the pharmaceutical development that we are and what hope that could offer.”
The Patient Journey
If approved, how would treatment with pharmaceutical LSD actually work? Dr. Karlin outlines a patient journey starkly different from picking up a 30-day prescription at a pharmacy.
Initially, eligibility would likely be for patients who have not found success with two or more existing standard treatments. Treatment would not occur in a typical outpatient office. “They would be referred to some sort of specialty treatment center, interventional psychiatry center,” Karlin explains, noting the need for monitoring during the acute drug effects.
The treatment day itself would be structured. After an assessment, the patient would take a sublingual tablet. “The effects of the drug… come on over about a half hour,” with peak effects lasting several hours, and the acute experience resolving over approximately 6-8 hours. Crucially, the therapeutic aim is not the acute experience itself, but the lasting change that follows. “In many cases what people have already begun to feel is different with regard to their illness even by the end of the session.”
Following the session, patients would have follow-up visits to support integration and monitor response. The hope, based on clinical trial data, is for a sustained period of response or remission without needing another dose. “That period of response or remission would persist for a time period… someone may or may not have a return of symptoms at some point in the future,” at which point a repeat treatment could be considered. This model—a focused, intensive intervention followed by a prolonged treatment-free interval—represents a fundamental shift from chronic daily pharmacotherapy.
Paving the Way for a New Treatment Model
Introducing a therapy that requires a dedicated, all-day clinical visit with medical monitoring presents systemic challenges. Dr. Karlin acknowledges this, comparing it to precedents in other areas of medicine. “There are plenty of treatments that are given in other therapeutic areas that involve monitoring and observation and changing people’s sensorium. So nothing is completely new, but it is new in total to psychiatry.”
He identifies two parallel tracks: securing FDA approval based on safety and efficacy data, and working with healthcare systems and payers to prepare for implementation.” That work, fortunately, can be done in parallel… being able to understand the implications that the drug would have on practice patterns and on payment patterns… is very much something that we’re able to do now.” Success will depend not only on convincing regulators but also on demonstrating to insurers and providers that the potential for durable remission justifies the upfront resource intensity of treatment.
Redefining Goals in Psychiatry
Beyond treating individual disorders, Dr. Karlin sees a broader potential impact for psychedelic medicine on the field of psychiatry itself. He argues that the dominant model of symptom suppression has led to diminished expectations. “The SRI and second-generation antipsychotic era of psychiatry has led us to aim too low, I think, to think just in terms of symptom suppression.”
The psychedelic model, with its focus on catalyzing lasting psychological change, points toward more ambitious goals. “It can and should be living their best life, seeking satisfaction in a way that makes sense to them. Self-actualization. There are all these higher principles than just symptom suppression.” If successful, Karlin posits, psychedelic-assisted therapy could help refocus psychiatry on these higher-order outcomes, measuring success not just by a reduction in symptom scores but by improved quality of life and psychosocial functioning.
A Rigorous Path Forward
The journey of LSD from a tool of mid-century psychotherapy to a banned substance and now to a late-stage pharmaceutical candidate is a remarkable narrative of scientific revival. As Dr. Karlin summarizes, “Definium is bold and scientifically rigorous and we’re bringing that to this old drug that shows so much promise… by using modern scientific methods and by being extraordinarily rigorous in our science… we’re redefining the potential for this very old thing… and making it new.”
The coming years will be critical. Data readouts from Definium’s and other companies’ Phase III trials will provide definitive evidence on whether the significant promise observed in earlier, smaller studies translates into large-scale, reproducible efficacy and safety. Regulatory reviews will test the frameworks for evaluating these novel treatment models. Healthcare systems will grapple with practical and economic integration.
What is clear is that the psychedelic renaissance has moved firmly into the mainstream of biopharmaceutical research. Driven by unmet patient need, evolving science, and a new generation of companies applying rigorous methodology, this field is no longer about counterculture but about constructing a new, evidence-based option for the millions for whom current treatments fall short. The goal, as articulated by Dr. Karlin and the Rerouting Minds campaign, is to steer the conversation—and potentially, mental healthcare itself—toward a new destination defined by durable recovery and renewed hope.
