Frontiers in Neuroscience
February 4, 2020
Claire J. Foldi, Paul Liknaitzky, M.l. Williams et al.
52 citations
Anorexia nervosa has the highest mortality rate of any psychiatric disease, and current medications are largely ineffective partly because the neurobiological drivers are poorly understood. Recent research into psychedelic medicine suggests psilocybin may alleviate symptoms related to serotonin signaling and cognitive inflexibility. Clinical trials for treatment-resistant depression show promise but have methodological biases. The first clinical trial using psilocybin for anorexia nervosa began in 2019, highlighting the need to understand the neurobiological mechanisms. Animal models, such as the activity-based anorexia rodent model, allow detailed study of brain function and behavior without the confounds of expectancy and bias, and are argued to be crucial for informing which patient subpopulations may benefit most from psychedelic medicine.
Endocrinology
July 1, 2024
Sheida Shadani, Kyna Conn, Zane B. Andrews et al.
49 citations
The resurgence of interest in psychedelics as psychiatric treatments highlights a need to understand potential sex differences in response. Human studies show efficacy across diagnoses and cognition, but sex-specific effects remain unclear. Animal studies often use one sex or fail to analyze sex differences, hindering translation. Estrogen interacts with the serotonin system, central to psychedelic action, by influencing serotonin synthesis, release, and receptor sensitivity. This interaction may alter psychedelic efficacy in females across menstrual cycles and developmental stages. Investigating estrogen-serotonin interactions could improve therapeutic outcomes, especially for conditions with sex-specific prevalence.
Trends in Pharmacological Sciences
February 1, 2024
Felicia Reed, Claire J. Foldi
22 citations
Psilocybin, a psychedelic compound being tested as a treatment for mental health conditions, strongly activates serotonin receptors found not only in the brain but also in the gastrointestinal tract. Despite evidence that gut-brain signaling is disrupted in conditions where psilocybin is used, no research has examined whether its effects on the gut contribute to mental health improvements. This opinion piece argues that psilocybin's peripheral actions in the gut may play a role in its rapid and lasting therapeutic effects, and that understanding all sites of action could guide more targeted drug development.
Translational Psychiatry
September 30, 2024
Elizabeth L. Fisher, Ryan Smith, Kyna Conn et al.
14 citations
Psilocybin treatment in rats performing a reversal learning task led to more rewards through increased task engagement, driven by changes in forgetting rates and reduced loss aversion. Computational modeling suggests psilocybin may induce an optimism bias by altering how beliefs are updated, which could have implications for clinical conditions marked by pessimism.
bioRxiv (Cold Spring Harbor Laboratory)
December 13, 2023
Kyna‐anne Conn, Lk Milton, Kaixin Huang et al.
6 citations
preprint
In a rat model of anorexia nervosa (activity-based anorexia), psilocybin improved body weight maintenance and facilitated cognitive flexibility, particularly by enhancing adaptation when reward contingencies were reversed. The cognitive benefits depended on signaling through the serotonin 5-HT1A receptor, as blocking that receptor negated the effects. Psilocybin also transiently altered cortical expression of serotonin receptor genes, increasing Htr2a and decreasing Htr1a transcripts, with a further reduction in Htr2a in anorexic-model rats. These findings suggest psilocybin could help break cognitive inflexibility in anorexia nervosa and indicate that therapeutic mechanisms may extend beyond 5-HT2A receptor binding.
Physiology & Behavior
May 20, 2025
Kaspar McCoy, Felicia Reed, Kyna‐anne Conn et al.
4 citations
Psilocybin, a serotonergic psychedelic, shows promise for treating anorexia nervosa by enhancing cognitive flexibility and modifying reward processing—two core processes disrupted in the disorder. Its effects are primarily mediated by the 5-HT2A receptor, but recent evidence indicates broader interactions with dopaminergic pathways in brain regions like the prefrontal cortex and nucleus accumbens. Rodent models demonstrate that psilocybin induces rapid and enduring neuroplastic changes, improving cognitive flexibility through complex neurochemical mechanisms. Advances in real-time neurochemical recording now allow simultaneous monitoring of serotonin and dopamine signaling, which will provide insights into their coordinated actions during cognitive performance. Further research into psilocybin's dual modulation of these systems is needed to optimize therapeutic applications for anorexia nervosa.
bioRxiv (Cold Spring Harbor Laboratory)
May 17, 2024
Elizabeth L. Fisher, Ryan Smith, Andrew W. Corcoran et al.
2 citations
preprint
Rats treated with psilocybin achieved more rewards in a decision-making task, driven by increased task engagement, altered forgetting rates, and reduced loss aversion. Computational modeling of the rats' behavior revealed that psilocybin may induce an optimism bias through changes in how beliefs are updated. This finding has potential relevance for clinical populations characterized by a lack of optimism, such as those with depression.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 25, 2026
Sheida Shadani, Kaspar McCoy, Lina Ong et al.
A single dose of psilocybin (1.5 mg/kg) in C57BL/6 J mice produces sex-specific effects on social behavior and dopamine signaling. In females, psilocybin acutely increased huddling and induced hypothermia, and post-acutely enhanced novelty-seeking and grooming, with no comparable effects in males. By 24 hours, males showed reduced grooming and rearing but increased sociability toward a cage-mate, accompanied by blunted novelty-evoked nucleus accumbens dopamine responses lasting up to 7 days. At 7 days, females shifted social preference toward familiarity, associated with prolonged dopamine release during familiar interactions, while males increased grooming. Both 5-HT1A and 5-HT2A receptors contributed to these sex-specific behavioral effects.
bioRxiv
May 18, 2026
Kyna Conn, Ngok Wong, Serenay Sunnetci et al.
A single dose of psilocybin (1.5 mg/kg) in female rats enhanced cognitive flexibility in several learning tasks by amplifying dopamine signals in the nucleus accumbens. The drug increased learning rates and reduced reliance on prior expectations, leading to faster reversal learning. However, calorie restriction and prior exposure to activity-based anorexia (ABA) reduced these benefits. Calorie restriction shifted the timing of psilocybin's effect on reversal learning and increased neural activity in the nucleus accumbens. Prior ABA exposure eliminated improvements in discrimination accuracy and trended toward worsening reversal learning, likely due to reduced cortical 5-HT2A receptor availability. The results show that nutritional state and history of anorexia-like behavior critically moderate psilocybin's cognitive effects.
Translational Psychiatry
April 14, 2026
Ryan J. Keenan, Rifa T Haque, Xiangjun Jin et al.
A single dose of psilocybin worsened diet-induced weight loss over four weeks in obese mice switched to low-fat chow, making them more likely to lose more weight. The effect came mainly from reducing food intake, not from changing energy expenditure. In obese mice kept on a high-fat diet, psilocybin did not affect body weight or food intake, suggesting it does not directly cause weight loss or reduce eating. Instead, it may help enable weight loss when combined with other weight-loss interventions. The findings support further research into psychedelic compounds as an add-on therapy for obesity, though more work is needed to understand the mechanisms.
Psychedelics.
February 3, 2026
Sheida Shadani, Erika Greaves, Zane B. Andrews et al.
Psilocybin did not alter sociability in female mice under metabolic stressors—activity-based anorexia, food restriction, or running wheels—but increased preference for social familiarity (reduced novelty-seeking) in control mice. Both activity-based anorexia and running wheel groups showed elevated novelty-seeking behavior, though with distinct social patterns. Psilocybin raised levels of the proinflammatory cytokine interleukin-6 (IL-6) in running wheel mice, and that increase correlated with preference for novelty; no such relationship appeared in the other groups. These context-dependent effects on social behavior and inflammation highlight the need for further research on psilocybin's mechanisms across sexes and disease models.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2025
Sheida Shadani, Kaspar McCoy, Lina Ong et al.
A single dose of psilocybin (1.5 mg/kg) alters social behaviors in C57BL/6J mice in sex-specific ways. In females, psilocybin acutely triggers huddling linked to body temperature changes, enhances preference for social novelty 4 hours after administration lasting about 24 hours, but reverses to a preference for familiar over novel conspecifics 7 days later, associated with prolonged nucleus accumbens dopamine signaling during familiar sniffing. In males, psilocybin reduces stress-related behaviors at 24 hours and increases preference for familiar conspecifics, with blunted novelty-evoked dopamine responses at both 24 hours and 7 days. Both 5-HT1A and 5-HT2A receptors modulate these behaviors in sex-specific ways. The prosocial effects of psychedelics are not universal, emphasizing the need for sex-informed approaches.
bioRxiv (Cold Spring Harbor Laboratory)
October 15, 2025
Sheida Shadani, Erika Greaves, Zane B. Andrews et al.
preprint
A single dose of psilocybin did not alter sociability in female mice exposed to activity-based anorexia, food restriction, or exercise, but increased preference for familiarity in control mice. Novelty-seeking behavior rose in both anorexia-model and exercise mice, with distinct social patterns. Psilocybin elevated the inflammatory marker interleukin-6 in exercised mice, which correlated with novelty preference; no such link appeared in other groups. These context-dependent effects on social behavior and inflammation underscore the need to study psilocybin's mechanisms across sexes and disease models.
The International Journal of Neuropsychopharmacology
August 1, 2025
Nicolo Fabila, Nimshitha Pavathuparambil Abdul Manaph, V Rudkowsky et al.
Psilocybin, at a dose of 2 mg/kg, did not reduce compulsive eating in a rat model of binge eating disorder. Female rats given intermittent access to a high-fat/high-sugar diet for 10 weeks showed no change in how quickly they started eating or how much they ate after psilocybin treatment, compared to saline. The compound may have affected freezing behavior, suggesting possible modulation of fear-related learning and memory circuits, though analysis is ongoing. Binge eating disorder is the most common eating disorder and current treatments are limited. Psilocybin is known to promote neuroplasticity, but at this dose it did not alter compulsive-like eating behavior in the conditioned suppression test.
March 31, 2025
Ryan J. Keenan, Rezaul Haque, Xianbo Jin et al.
A single dose of psilocybin exacerbated diet-induced weight loss over four weeks in diet-induced obese mice switched to low-fat chow, increasing susceptibility to more profound weight loss. Psilocybin modulated food intake without affecting energy expenditure. No changes in body weight or food intake occurred in mice maintained on a high-fat diet, indicating psilocybin does not directly promote weight loss or reduce food intake but may facilitate weight loss when combined with other interventions. The findings support further investigation of psychedelic compounds as an adjunct therapy for obesity.
Focus (American Psychiatric Publishing)
July 1, 2024
Claire J. Foldi, Paul Liknaitzky, Martin L Williams et al.
Anorexia nervosa has the highest death rate of any psychiatric illness, but current medications are largely ineffective partly because the neurobiological causes are poorly understood. Renewed research into psychedelic medicine, particularly psilocybin, suggests it may help symptoms related to serotonin signaling and cognitive inflexibility in anorexia nervosa. Clinical trials for treatment-resistant depression show promising results, though methodological biases remain. The first clinical trial of psilocybin in anorexia nervosa patients began in 2019, highlighting the need to understand the underlying neurobiological mechanisms. Animal models, such as the activity-based anorexia rodent model, can provide detailed brain and behavior analysis without the confounds of patient expectancy and bias. The authors argue such studies are crucial for informing clinical applications and identifying which patient subpopulations might benefit most.
October 9, 2022
Claire J. Foldi
Psychedelics such as psilocybin, the psychoactive compound in magic mushrooms, show promise for treating anorexia nervosa, but they are not effective for everyone. Researchers are using lab rats to study how these drugs might work, aiming to uncover mechanisms that could improve treatment for this eating disorder.