Chronic Treatment With Psilocybin Decreases Changes in Body Weight in a Rodent Model of Obesity

Hutson and colleagues frame the study within the longstanding interest in serotonergic agents as anti-obesity treatments. They note that drugs which raise synaptic serotonin or act at specific serotonin receptors (notably 5-HT1B, 5-HT2C and 5-HT6) have historically reduced feeding and body weight, but many such agents were withdrawn because of adverse effects. Psilocybin, metabolised to the active compound psilocin, is an agonist at multiple serotonin receptors and has become of interest because of its safety profile in human research and associations in epidemiological data with lower odds of overweight/obesity and improved cardiometabolic self-reports. The authors therefore identify a gap: whether chronic administration of psilocybin can modulate weight gain in a controlled preclinical model of obesity. The present study aimed to determine whether repeated administration of psilocybin alters weight gain in a validated rodent model of diet-induced obesity. Using a cafeteria diet to induce obesity in Sprague-Dawley rats, the investigators compared three doses of psilocybin (0.1, 1 and 5 mg/kg) against an oral metformin positive control (300 mg/kg) and a vehicle control over 27 weekday treatments. Outcome measures included relative change in body weight, consumption of the high-calorie diet, fasting glucose, glucose tolerance and fat-pad measures of adiposity. The authors justify the approach by noting the translational predictive validity of rodent obesity paradigms for human weight outcomes and include a “microdose” condition to reflect emerging interest in sub-perceptual dosing.

Ninety adult male Sprague-Dawley rats (275–300 g) were acclimated and then given ad libitum access to both standard rat chow and a high-calorie cafeteria diet until reaching approximately 600 g. Animals were pair-housed on a reverse light cycle and stratified by body weight into treatment groups. Treatments were administered daily Monday–Friday for a total of 27 drug treatment days; weekend access and feeding were handled by animal-care staff because of COVID-19 restrictions, so chow intake on weekends was not measured by the research team. Five treatment conditions were planned: psilocybin at 0.1, 1.0 and 5.0 mg/kg dissolved in sterile saline and given by intraperitoneal (IP) injection, an oral gavage of metformin at 300 mg/kg, and vehicle control. Solutions were prepared fresh daily and administered in a volume of 1 ml/kg; IP injection sites were rotated. Psilocybin was given IP because of limited data on oral dosing in rats. The medium-dose psilocybin (1 mg/kg) group was terminated early after an accidental incorrect treatment at midpoint; their mid-study data are reported for informational purposes only. The cafeteria diet was a palatable paste composed chiefly of crackers, chocolate hazelnut spread and peanut butter, supplemented with mini-marshmallows and crushed chips on weekdays; nutritional values were calculated from commercial sources. Primary outcomes were relative change in body weight (percent change from baseline) and relative food consumption (food consumed as percent of body weight), measured daily on weekdays. Secondary physiological measures were fasting blood glucose measured pre-treatment, after 10–11 days, and at study end; an intraperitoneal glucose tolerance test (IGTT) after an overnight fast at study end with measurements at 60 and 120 minutes; and dissection and weighing of fat pads (subcutaneous, left retroperitoneal and left perirenal) normalized to body weight. Longitudinal outcomes were analysed by repeated-measures ANOVA, non-longitudinal continuous data by t-test or one-way ANOVA, and associations by Pearson correlation. Fisher's exact test was used for categorical comparisons with small cell counts. Significance was set at p < 0.05 and Fisher's LSD used for post-hoc comparisons.

Rats were fed the cafeteria diet for 51 days prior to treatment and, at baseline, cafeteria-fed groups weighed more than the standard chow control (mean 609.7 g vs 548.6 g; overall group difference F(5,87)=3.11, p < 0.05). The medium-dose psilocybin group was removed after an incorrect administration; their available midpoint data are reported only for information. Analysis of relative weight gain across the 27 treatment days showed significant effects of drug treatment [F(4,68)=6.92, p < 0.001], time [F(26,1768)=261.359, p < 0.001], and a drug-by-time interaction [F(104,1768)=3.391, p < 0.001]. Post-hoc tests indicated that the high-calorie diet control group exhibited the greatest relative weight gain. The low-dose psilocybin group (0.1 mg/kg) had significantly less relative weight gain than the high-calorie control (p < 0.05), and the high-dose psilocybin group (5 mg/kg) also showed reduced relative weight gain (p < 0.01). Metformin produced the largest reduction in relative weight gain compared with all other high-calorie diet groups (p < 0.05). Exploratory day-by-day analyses suggested rapid onset of effect, with reduced relative weight gain evident by day 2 for the medium- and high-dose psilocybin groups and for metformin. When relative food consumption (percent of body weight) was analysed over the full treatment period, there was no significant main effect of drug treatment [F(3,55)=1.990, p=0.126], although time was significant [F(24,1320)=4.782, p < 0.001]. Follow-up comparisons based on a priori predictions showed that both the metformin and high-dose psilocybin groups consumed relatively less of the high-calorie diet than controls across the treatment period (p < 0.05). Analysing consumption in shorter bins revealed a significant group effect for days 1–6 [F(4,73)=3.12, p < 0.01] and a trend for days 7–13 [F(4,73)=2.32, p = 0.06], with differences disappearing later in treatment. From days 1–6, mean consumption (percent of body weight) was: control 3.22 ± 0.14%, low psilocybin 2.79 ± 0.13%, high psilocybin 2.81 ± 0.13%, and metformin 2.64 ± 0.14%. Total caloric intake over the treatment period followed the same pattern (control 4430.9 ± 221.5 kcal; low psilocybin 4145.9 ± 211.5 kcal; high psilocybin 3955.5 ± 233.2 kcal; metformin 3705.7 ± 130.9 kcal). The ANOVA for total calories did not reach significance [F(3,55)=2.04, p=0.120], but metformin consumed significantly fewer calories than vehicle control (p < 0.05). Only the metformin group left mini-marshmallows uneaten (115 total over treatment; p < 0.001 vs others). Fasting glucose at the midpoint did not differ between groups [F(5,87)=1.736, p=0.136]. In the IGTT at study end, the normal diet (no cafeteria access) group showed significantly lower glucose levels than all high-calorie groups, particularly at the 1 h timepoint; no differences were observed among the high-calorie diet groups. Fat-pad analyses normalised to body weight showed no group difference for perirenal fat [F(4,72)=0.995, ns], but significant group effects for subcutaneous [F(4,72)=3.089, p < 0.05] and retroperitoneal fat [F(4,72)=10.282, p < 0.001]. Post-hoc comparisons indicated that for subcutaneous fat the normal diet group differed from the high-calorie groups except metformin, while for retroperitoneal fat the normal diet, high-dose psilocybin and metformin groups had lower relative adiposity than the high-calorie control. Correlational analyses found that subcutaneous (r = 0.528, p < 0.001) and retroperitoneal fat (r = 0.544, p < 0.001) were associated with glucose intolerance at 1 h, whereas perirenal fat was not. Total relative weight gain correlated with subcutaneous and retroperitoneal adiposity and correlated strongly with total high-calorie diet consumed (r = 0.666, p < 0.001).

Hutson and colleagues interpret their principal finding as evidence that chronic psilocybin treatment produced modest but significant reductions in relative weight gain in a rat model of diet-induced obesity. Both the low (0.1 mg/kg) and high (5 mg/kg) psilocybin doses slowed weight gain relative to high-calorie diet controls, and metformin produced a larger effect than either psilocybin dose. The high-dose psilocybin and metformin groups also showed reduced intake of the high-calorie diet, particularly during the first two weeks, and both had lower relative central adiposity than the high-calorie controls. No drug treatment altered fasting glucose or glucose tolerance among the high-calorie groups, with the IGTT differences largely reflecting the lean normal-diet control group. The authors caution that “slowed weight gain” rather than absolute weight loss is a common outcome in rodent obesity models because laboratory rats generally gain weight across their lifespan; therefore relative reductions in weight gain in drug-treated animals are how preclinical efficacy is commonly manifested and interpreted for translational purposes. They note uncertainties about dose equivalence across species: allometric scaling yields human-equivalent doses of approximately 0.016, 0.16 and 0.81 mg/kg for the rat doses used, and IP administration may provide greater bioavailability than oral dosing. The medium 1 mg/kg dose used in some behavioural studies was accidentally discontinued here, and the authors acknowledge that their highest dose may already exceed typical clinical human exposures when adjusted, underscoring the need for pharmacokinetic data in future comparisons. Mechanistically, the authors highlight that psilocin acts at 5-HT2C as well as 5-HT2A and 5-HT1A receptors, and that 5-HT2C agonism is a plausible pathway to reduce feeding and influence glucose homeostasis. They point out that the low “microdose” (0.1 mg/kg) decreased weight gain without a detectable reduction in measured cafeteria food intake, which could reflect effects on metabolism, energy expenditure or selective macronutrient intake—though the study could not resolve intake of standard chow on weekends or selectivity among macronutrients because the cafeteria diet was homogenised into a paste. Several limitations are acknowledged. The study did not investigate molecular or neural mechanisms; only male rats were used, limiting generalisability across sexes; the highest psilocybin dose may not map straightforwardly onto human-relevant doses; and chronic weekday dosing may induce tolerance (including 5-HT2A downregulation) unlike the intermittent dosing strategies used in many human psychedelic trials. Practical constraints arising from COVID-19 staffing meant weekend chow intake was not measured, complicating full dietary intake assessment. The authors recommend further work using pharmacokinetic measures, higher or varied dosing schedules, intermittent dosing to reduce tolerance, inclusion of female animals, and testing in alternative metabolic models (for example the Zucker rat) to probe diabetes-related endpoints and mechanisms. Overall, the study presents preliminary preclinical evidence that psilocybin can modestly slow weight gain and reduce central adiposity in this model. The authors emphasise that effects were smaller than those produced by metformin in the present protocol and that safety, dosing equivalence and mechanistic questions remain to be resolved before translational inferences can be made. They conclude that further investigation is warranted.