Lysergic acid diethylamide (LSD) has joined a growing list of potent serotonergic system psychedelics that have emerged as promising treatments for some psychiatric disorders, including major depressive disorder, anxiety disorders, and substance use disorders. Like other psychedelics, a single administration can produce therapeutic benefits that can persist for months, suggesting that LSD may have induced lasting changes in brain function. Animal studies suggest that these benefits are driven by changes in dendritic growth, synaptic plasticity, and neurotrophin (brain hormone) expression. LSD is thought to open a critical learning period, characterized by increased aspects of neuroplasticity, in which learning is more efficient for at least a few days after dosing (for more about LSD’s actions in the brain, read Your Brain on Food, How Chemicals Control Your Thoughts and Feelings).
Evidence of these changes in human subjects remains relatively limited. Little is known about how brain function and behavior evolve in the days following a single drug administration. A recent study investigated the lasting effects of LSD on motor learning and perceptual processing. Motor learning was assessed using a sequence typing task capturing both online learning during active practice and offline consolidation following practice. Perceptual processing was determined by examining the neurophysiological effects using auditory tetanization with electroencephalography and paired associative stimulation with transcranial magnetic stimulation. In addition, self-report measures included questionnaires on perceived stress and cognitive flexibility. Together, these approaches allowed the authors to characterize acute and longer-term effects on perceptual processing, motor learning, and psychological functioning for up to one week after a single dose of LSD in healthy subjects. Blood levels of the neurotrophin BDNF were determined to assess possible longer-term effects of LSD on this hormone that is known to be critical for the maintenance of neuroplasticity.
This highly rigourous study used a randomized, double-blind crossover design. Forty-five healthy participants between the ages of 21 and 55 received one dose of 100µg LSD and one inactive placebo.
This is the first study using healthy human subjects to demonstrate improvements in motor learning after a psychedelic drug. Overall, LSD induced mostly positive acute and lasting subjective effects, as well as transient side effects. As predicted by similar studies using psilocybin, LSD induced changes in neural activity that are associated with the disruption of early sensory processing and attentional allocation. Essentially, this is what is expected when the subjects are creating internally generated sensory signals, i.e., they’re hallucinating (Kometer et al., 2011). Acutely, LSD impaired the ability of the subjects to pay attention to salient or novel sensory inputs. LSD treatment also commonly causes muscle tension and shaking during its peak drug effects; the mechanisms underlying this effect are well known. Finally, there was no effect of LSD on BDNF levels. The lasting changes in brain function must depend upon changes in other neurotrophins.
The day after dosing, the subjects who received LSD showed significant selective improvements in motor memory consolidation. This change was specific to improvements in speed. There was no change in accuracy, suggesting that the effect on speed does not simply reflect a speed-accuracy trade-off. The authors speculated that these improvements showed either enhanced neuroplasticity or possibly the post-drug exposure effects on motivation, attention, and/or arousal of the subjects.
Animals given LSD also show improved motor skills and improved performance across different learning paradigms, including classical and operant conditioning, fear extinction, and social reward learning. An earlier study using human subjects (Ornelas et al., 2022) reported improvements in visuospatial learning and memory consolidation the day after dosing only 50µg of LSD. These findings mirror those discovered using animal studies and suggest that a single treatment with LSD may broadly enhance synaptic plasticity in brain regions critical for learning and paying attention. How long these benefits last remains to be determined.