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Key points
- 50 years of LSD research transformed neuroscience by revealing serotonin and neuroplasticity.
- A single supervised LSD dose may briefly enhance learning and brain adaptability beyond intoxication.
- LSD shows promise for anxiety treatment, but careful clinical science must guide its future.
Could LSD treat common psychiatric disorders like generalized anxiety disorder or major depression? It sounds almost absurd considering LSD’s long-standing reputation as psychiatry’s “wicked witch”—a drug previously viewed as too dangerous, controversial, and politically radioactive to study. Yet that is precisely where the new data are leading
In June 2026, Abigail Calder and colleagues added another piece to this story, reporting in Neuropsychopharmacology that LSD can alter learning in healthy human volunteers. The study was not a treatment trial, but it asks whether LSD produces changes in brain function that can reopen windows of learning, adaptation, and plasticity
Early in my career, we viewed LSD primarily as a pharmacologic model of schizophrenia, hoping it would illuminate the biology of severe mental illness. Today’s researchers, armed with state-of-the-art neuroimaging, electrophysiology, and carefully designed clinical trials, are asking a far more ambitious question: Can the transient changes produced by LSD reveal how the adult brain learns, adapts, and perhaps even heals itself?
My introduction to LSD research came at Yale, where I worked with the late George Aghajanian, who himself had been mentored by Daniel X. Freedman. Together, they helped move LSD from a pharmacologic model of psychosis toward a scientific tool to understand serotonin, perception, and normal brain function. Their work helped launch modern neuropsychopharmacology and shifted the field from describing bizarre behavior to investigating underlying brain mechanisms
More than 50 years later, Calder and colleagues revisited a question that would have been impossible to answer during the Yale era. Healthy volunteers received either a supervised 100-µg dose of LSD or a placebo. Rather than focusing on the acute psychedelic experience, investigators asked whether measurable changes in learning and brain function persisted after intoxication had resolved. The answer appeared to be yes
Participants exhibited improved offline motor learning—the brain’s capacity to consolidate new skills after practice—and reported greater mental flexibility and lower perceived stress one week later. The importance of the study lies less in any single finding than in the question it asks. Rather than asking whether LSD produces hallucinations, Calder and colleagues asked whether it temporarily creates a brain state favoring knowledge acquisition and behavioral adjustment
The adult brain is a constantly evolving organ, remodeling itself in response to experience. During the hours and days after administration of LSD, the subjects’ neural circuits continued strengthening some connections while weakening others in a process known as consolidation. This remarkable capacity for neuroplasticity enables the acquisition of new skills, the modification of behavior, the recovery from injury, and the adaptation throughout life. LSD appears to transiently reduce the rigidity of normal brain networks, allowing communication between regions that ordinarily remain independent.
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Rather than simply disrupting brain activity, these transient changes may create a brief window during which learning and behavioral change become easier
Whether this interpretation ultimately proves correct is unknown. Fifty years ago, investigators asked whether LSD resembled psychosis. Today, they are asking whether LSD can illuminate the brain’s remarkable capacity for neuroplasticity. This shift helps explain why psychiatrists have become interested in LSD once again—not simply as a psychedelic drug but as a possible therapeutic tool
Recent clinical trials of pharmaceutical LSD (MM120), which I discussed previously, have produced encouraging results in treating generalized anxiety disorder. These and other recent clinical findings offer one possible biological explanation for those findings. These findings shifted the conversation from whether LSD has therapeutic potential to howit might work
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Clinical trials suggest a single supervised dose of LSD may produce durable improvement in patients with generalized anxiety disorder, while early studies in major depression are also encouraging. These data remain preliminary but raise an interesting possibility: a temporary period of enhanced neuroplasticity may make entrenched patterns of thinking and behavior more amenable to change. Whether psychotherapy is important for maximizing that opportunity—or whether the biological state itself provides much of the benefit—remains an important unanswered question.
Among contemporary psychedelic therapies, LSD has developed one of the strongest emerging evidence bases for the treatment of generalized anxiety disorder (GAD). This represents a remarkable reversal from the drug’s reputation over the past half-century: the same compound once viewed a dangerous hallucinogen is now being evaluated in late-stage clinical trials for one of psychiatry’s most common disorders
The evidence for major depressive disorder is less mature but equally intriguing. Early clinical studies suggest that a single therapeutic dose may produce rapid antidepressant effects that last for weeks in some patients
Importantly, the Calder study does not demonstrate that LSD treats anxiety or depression. Instead, it provides something arguably just as valuable: a biological system to understand why and how psychedelic-assisted treatments might work
The question is no longer whether LSD produces profound psychological experiences. It is whether the temporary biological state it creates may itself promote recovery
The answer is still uncertain. Psychotherapy may ultimately be indispensable for maximizing and sustaining benefit in some patients. Also, carefully selected patients may improve with far less intensive psychological intervention than previously believed. Determining which patients benefit most—and under what therapeutic set and setting—has become one of the central questions facing psychedelic psychiatry
Other important scientific questions remain unanswered. Psychedelic trials remain uniquely vulnerable to functional unblinding because participants usually recognize when they have received the active drug, potentially influencing subjective outcomes. Long-term safety also requires continued study, especially with repeated exposure. Although there is currently no convincing evidence that one or two supervised therapeutic LSD sessions produce clinically significant cardiovascular injury, recent observational evidence has raised concern that repeated LSD exposure—including chronic microdosing—may be associated with serotonin 5-HT2B receptor-mediated valvular heart disease resembling the fenfluramine-associated valvulopathy recognized decades ago. While these findings require prospective confirmation and should not be interpreted as establishing causation, they reinforce the importance of long-term cardiovascular surveillance as psychedelic therapies move into clinical practice.
The 2026 Rand report estimated that approximately 3 million U.S. adults used illicit LSD during the previous year. These individuals are fundamentally different from participants enrolled in modern clinical trials, who undergo extensive psychiatric and medical screening and receive pharmaceutical-grade LSD in carefully controlled doses under continuous medical supervision. Outside research settings, users often self-administer LSD of uncertain identity, purity, potency, and cumulative exposure, frequently without medical oversight. The emerging evidence linking repeated LSD exposure to fenfluramine-like valvular heart disease is particularly relevant to chronic recreational use and microdosing, where cumulative dosing far exceeds that used in therapeutic protocols. Recreational use also continues to result in emergency department visits, psychiatric hospitalizations, accidental injuries, and exposure to counterfeit products sold as LSD. Consequently, the growing interest in psychedelic-assisted therapy should not be interpreted as evidence that unsupervised recreational use or self-directed microdosing is safe.
Conclusion
More than 50 years ago, investigators at Yale used LSD to understand serotonin. Today, researchers use it to study neuroplasticity. Whether LSD ultimately becomes an accepted psychiatric treatment is still uncertain. LSD’s greatest contribution may not be the psychedelic experience it produces, but instead the insights into how the human brain learns, adapts, and changes throughout life
Calder AE, Diehl VJ, Lietz MP, Yousefi P, Friedli N, Coviello F, Rouaud A, Beichmann K, Eckert A, Hasler G. Acute and post-acute neurobehavioral responses to lysergic acid diethylamide in healthy subjects: a randomized controlled study. Neuropsychopharmacology. 2026 Jun 18. doi: 10.1038/s41386-026-02454-7. Epub ahead of print. PMID: 42315644
George K. Aghajanian, Marek GJ. Serotonin and hallucinogens. Neuropsychopharmacology. 1999;21(2 suppl):16S-23S
Williams ZJ, Barnett H, Szigeti B. Psychedelic therapy vs antidepressants for the treatment of depression under equal unblinding conditions: a systematic review and meta-analysis. JAMA Psychiatry. 2026;83(5):461-468
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Williams ZJ, Barnett H, Szigeti B. Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2026;83(5):461–468. doi:10.1001/jamapsychiatry.2025.4809
Shinozuka K, Tewarie PKB, Luppi A, Lynn C, Roseman L, Muthukumaraswamy S, Nutt DJ, Carhart-Harris R, Deco G, Kringelbach ML. LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics. Imaging Neurosci (Camb). 2025 Jan 3;3:imag_a_00420. doi: 10.1162/imag_a_00420. PMID: 40800760; PMCID: PMC12319965
Weiss F, Magnesa A, Gambini M, Gurrieri R, Annuzzi E, Elefante C, Perugi G, Marazziti D. Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. Brain Sci. 2025 Jan 25;15(2):117. doi: 10.3390/brainsci15020117. PMID: 40002450; PMCID: PMC11853016
