Psychedelics are being investigated as potential therapeutic compounds for the treatment of neuropsychiatric conditions such as posttraumatic stress disorder (PTSD), substance use disorders, and depression. These compounds are believed to reverse stress-induced damage in the prefrontal cortex (PFC), a region critical for executive functions, including cognitive flexibility. In rodents, reversal learning tasks are used to study the disruption in flexibility associated with several diseases.
A recent animal study published in Psychedelics used a selective serotonin 2A receptor agonist, 25CN-NBOH, a psychedelic agent that stimulates synaptogenesis and behavioral alterations. The authors tested and investigated whether a single dose of this agent could improve cognitive flexibility in mice.
A total of 27 male and female C57BL/6 mice with a mean age of 6 months were included in this study. Data from one mouse was excluded due to a lack of interaction with the Feeding Experimentation Device version 3 (FED3) device. Mice received an intraperitoneal injection of either saline (control, n = 14) or 10 mg/kg 25CN-NBOH dissolved in saline (n = 12). After 5 days of training with the FED3 device, mice underwent sequential fixed-ratio 2 (SEQFR2)-forward for 6 days (4 hours/day) and SEQFR2-reversal phases for six more days (4 hours/day) to assess flexible learning. The behavior of mice was determined by using poke efficiency, cumulative pellets, and percent correct. Statistical analysis was performed using multiple regression and Welch’s tests using Prism GraphPad (version 10.3.0) and R.
Psychedelic treatment did not affect forward learning poke efficiency (control R2 = 0.25, NBOH R2 = 0.20; F(1,557) = 0.1721, P = 0.6784) or percent correct (control R2 = 0.16, NBOH R2 = 0.13; F(1,431) = 0.7771, P = 0.3785) in both NBOH and control groups. However, NBOH-treated mice accumulated more pallets compared to control mice (control: R2 = 0.18, NBOH: R2 = 0.27; F(1,620) = 7.513, P = 0.0063), suggesting that increased trial initiation per hour, despite similar baseline and learning rates across groups.
Notably, psychedelic treatment significantly enhanced learning during the reversal phase, which was measured 15-20 days after a single administration. This was reflected by increased poke efficiency (control: R2 = 0.11, NBOH: R2 = 0.32; F(1,528) = 21.91, P < 0.0001), higher percent correct (control: R2 = 0.16, NBOH R2 = 0.13; F(1,431) = 0.7771, P = 0.3785) and greater accumulation of pellets (control: R2 = 0.18, NBOH: R2 = 0.27; F(1,620) = 7.513, P = 0.0063).
Welch’s one-sided t-tests revealed that NBOH-treated mice performed significantly better compared to controls during the reversal phase in both poke efficiency (t(17.40) = 2.29, p = 0.017, Cohen’s d = 0.928) and percent correct (t(22.92) = 2.07, p = 0.0252, Cohen’s d = 0.814). In contrast, no significant differences were observed between groups during the forward learning phase for poke efficiency (t(22.58) = 0.380, p = 0.354, Cohen’s d = 0.152) and percent correct (t(23.78) = −0.729, p = 0.763, Cohen’s d = -0.286).
Among saline-treated mice, males performed slightly better in poke efficiency than female mice during both forward (P = 0.0011) and reversal phases (P = 0.0218). Additionally, NBOH-treated male mice performed better in poke efficiency during the reversal phase than female mice (P = 0.0206).
In conclusion, this study’s findings support cellular evidence of psychedelic-induced brain changes in the PFC and reveal lasting cognitive benefits weeks after a single dose. Testing psychedelic effects on cognitive flexibility holds significant potential for treating conditions like Alzheimer’s disease, PTSD, and depression.
Reference: Brouns EJ, Ekins TG, Ahmed OJ. Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration. Psychedelics. 2025;1–7. doi:10.61373/pp025r.0002
