Pure psilocybin reduces reward-associated preference while mushroom extract shows transient exploratory effects in rats
Andreia Machado Brito-Da-Costa, Francisco Sacadura, Ricardo Jorge Dinis-Oliveira, Áurea Madureira-Carvalho, Diana Dias Da Silva
RevSALUS - Revista Científica da Rede Académica das Ciências da Saúde da Lusofonia May 1, 2026 DOI: 10.51126/revsalus.v8isupii.46826 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled preclinical experiment (conditioned place preference) Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Male Wistar Han rats weighing 250-275 g |
| Interventions | Psilocybin Psilocybe cubensis extract |
| Dose | 3 mg kg⁻¹ (pure psilocybin); 3 mg kg⁻¹ psilocybin/psilocin (P. cubensis extract) |
| Duration | Post-conditioning preference evaluated at 1, 7, and 14 days after the last treatment |
| Measures | conditioned place preference (CPP) scores, number of compartment entries |
| Topics | Psilocybin |
| Key findings | Pure psilocybin (3 mg/kg, oral gavage) significantly reduced conditioned place preference scores at 1 and 7 days post-treatment versus controls, indicating aversive or non-reinforcing effects, while a Psilocybe cubensis extract at the same psilocybin/psilocin dose produced no significant change in preference, with only a transient increase in entries into the drug-paired compartment at day 7. The authors argue the two treatments have distinct behavioral profiles, likely reflecting differences in bioactive composition. |
Abstract
Introduction: Psilocybin, the main psychoactive compound in Psilocybe mushrooms, has attracted interest for its potential therapeutic effects in neuropsychiatric disorders (Erkizia-Santamaría et al., 2025). However, preclinical data comparing its behavioral properties to whole mushroom extracts remain limited (Ali et al., 2023; Johnson-Groh, 2025).
Objective: To investigate the reinforcing and preference-related effects of these compounds, we evaluated pure psilocybin and Psilocybe cubensis extract in Wistar Han rats using a conditioned place preference (CPP) paradigm. Material and
Methods: Eighteen male Wistar Han rats (250–275 g) were randomly assigned to three groups (n=6): control (0.9 % NaCl), pure psilocybin (3 mg kg⁻¹), and P. cubensis extract (3 mg kg⁻¹ psilocybin/psilocin). Treatments were administered by oral gavage. Animals were confined to drug- or saline-paired compartments following a schedule to establish associative learning. Post-conditioning preference was evaluated at 1, 7, and 14 days after the last treatment. CPP scores were calculated as the fraction of time spent in the drug-paired compartment, and the number of entries into each compartment was recorded. Statistical analysis was performed using ANOVA with post hoc tests (p < 0.05). Results and
Discussion: Pure psilocybin significantly reduced CPP scores at 1- and 7-days post-treatment compared to controls, indicating aversive or non-reinforcing effects. No significant changes in CPP scores were observed for the mushroom extract group. Notably, the extract group showed a transient increase in entries into the drug-paired compartment on day 7, suggesting temporary exploratory interest, while the pure psilocybin group maintained fewer entries into the drug-paired compartment.
Conclusions: Pure psilocybin and P. cubensis extract elicited distinct behavioral profiles in the CPP test, likely reflecting differences in bioactive composition. The results highlight differential reinforcing properties of psilocybin alone versus the complex mushroom extract, providing valuable preclinical insight into their central effects.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |