Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice

Fadahunsi and colleagues frame obesity and addictive disorders as conditions that share neurobiological substrates, including persistent alterations in synaptic plasticity and reward-circuit dysfunction that can drive compulsive consumption. The serotonin system, and specifically signaling at the 5-HT2A receptor activated by psilocybin's metabolite psilocin, is implicated in both appetite regulation and neural plasticity; earlier preclinical and self-report data hinted that classic psychedelics might reduce consumption of rewarding substances or foods and thereby have therapeutic potential for disordered eating or obesity. Against this background, the study set out to evaluate whether psilocybin alters feeding behaviour, energy metabolism, body weight, or related transcriptional programmes in mice. The investigators tested acute and sub-chronic dosing regimens across multiple mouse models — diet-induced obese (DIO) mice, genetic obesity models (ob/ob and MC4R knockout mice), and an intermittent high-fat diet model that produces binge-like eating — and they profiled brain gene expression in the prefrontal cortex (PFC) and hypothalamus at 3 hours and 4 weeks after a single dose to probe both immediate and longer-term molecular effects.

The experimental work used male mice across several strains and models: wild-type C57BL/6J, leptin-deficient ob/ob, and melanocortin-4 receptor (MC4R) knockout mice. Diet-induced obesity was produced by switching C57BL/6J mice to a high-fat diet from 8 weeks of age. Animals were generally group-housed unless otherwise stated; mice were acclimatised and sham-injected prior to experiments. The Danish Animal Experimentation Inspectorate approved procedures. Psilocybin was prepared in isotonic saline and administered intraperitoneally. Dose-finding used the head-twitch response (HTR), a rodent behavioural proxy of 5-HT2A activation, testing 0.3, 1 and 3 mg/kg (HTR n = 4–5 per dose). The 3 mg/kg dose was selected for most in vivo metabolic and behavioural studies based on HTR and open-field outcomes. Other assays included an open-field test (locomotion and centre time; n = 8 per group), voluntary wheel running (n ≈ 7–8), indirect calorimetry in single-housed mice to measure oxygen consumption, respiratory exchange ratio, food and water intake (n = 8 per group), rectal body temperature time courses, and blood biochemistry (blood glucose, plasma corticosterone, cholesterol, triglycerides, insulin) with sampling at baseline, 3 h and 24 h as appropriate. Feeding and weight experiments comprised: single-dose studies in 46-week-old DIO mice (n = 8 per group) with 12 days follow-up, ob/ob mice (psilocybin n = 9; vehicle n = 7) with 7 days follow-up, a microdosing regimen (0.3 mg/kg daily) in a separate DIO cohort, and microdosing in MC4R KO mice. A dietary intervention experiment tested whether a single psilocybin injection given when high-fat diet (HFD) was replaced by chow could potentiate diet-induced weight loss (three groups, n = 8 each). A combinatorial pharmacological study assessed co-administration of daily liraglutide (GLP-1 receptor agonist) with a single psilocybin dose. Binge-like eating was modelled using an intermittent-access HFD protocol (intermittent group n = 19; continuous control n = 20); after establishing the phenotype mice received fluoxetine (30 mg/kg), psilocybin (3 mg/kg), or saline (n = 6 per treatment) and intake was measured at 2.5 and 24 h. Sucrose preference tests used 2% sucrose versus water with either a single 3 mg/kg dose (n = 10 per group) or repeated 0.3 mg/kg daily for 5 days (n = 8 per group). For molecular profiling, bulk RNA sequencing was performed on dissected PFC and whole hypothalamus from chow-fed mice treated with a single 3 mg/kg psilocybin or vehicle and sacrificed at 3 h or 4 weeks (four groups, n = 8 per group). Libraries were prepared using Illumina TruSeq and sequenced as 52-bp paired-end reads, yielding ~2.7 billion reads in total. Bioinformatic processing used STAR for alignment, featureCounts for quantification, voom/limma for differential expression modelling with extraction pool and duplicate-correlation accounted for, and gene-set enrichment via camera. Brown adipose tissue gene expression was measured by qPCR (delta-delta Ct, normalised to 36b4). Statistical analyses were performed in GraphPad Prism; all experiments reported were performed once and significance reported at P ≤ 0.05.

Dose-finding showed a typical head-twitch response: 1 and 3 mg/kg psilocybin produced more head-twitches than 0.3 mg/kg or vehicle (HTR n = 4–5). In the open-field test, mice given 3 mg/kg travelled a shorter distance and spent less time in the arena centre than saline-treated controls (n = 8), consistent with reduced locomotion and increased thigmotaxis after treatment. Voluntary wheel-running distance was not altered acutely or over five days after a single 3 mg/kg injection. Indirect calorimetry revealed no between-group differences in whole-body energy expenditure or substrate metabolism during the 5 days following a single 3 mg/kg injection (n = 8 per group). Psilocybin-treated mice showed a slight increase in cumulative food and water intake on a chow diet; increased water intake after 1 mg/kg was also observed in a DIO cohort. Rectal body temperature measured up to 24 h, brown adipose tissue thermogenic gene expression, blood glucose, plasma corticosterone (0, 3 and 24 h), total cholesterol, triglycerides and insulin (24 h) were not significantly different between psilocybin and vehicle groups. In multiple obesity models, psilocybin did not alter body weight or food intake. DIO mice given a single 3 mg/kg dose showed no differences in weight or intake over 12 days and no change in glucose tolerance on the final day (DIO n = 8 per group). Leptin-deficient ob/ob mice did not lose weight or reduce intake following a single 3 mg/kg dose (psilocybin n = 9; vehicle n = 7). A daily microdosing regimen (0.3 mg/kg) failed to affect body weight or food intake in DIO mice, and similar microdosing in MC4R knockout mice produced no change in weight or intake. Combining psilocybin with behavioural or pharmacological interventions produced null results for weight outcomes. In a dietary intervention where HFD was removed to induce weight loss, mice given psilocybin at diet switch did not maintain weight loss better than vehicle-treated controls. Liraglutide given daily produced approximately 9% body-weight loss after 7 days, but co-administration with a single psilocybin dose did not augment this effect. Behavioural paradigms for compulsive intake also yielded limited efficacy: in an intermittent-access binge-eating model, fluoxetine (30 mg/kg) reduced binge-like intake, whereas a single 3 mg/kg psilocybin did not. In contrast, a single 3 mg/kg injection reduced sucrose preference in lean mice without lowering water intake (sucrose preference study n = 10 per group). Repeated low-dose psilocybin (0.3 mg/kg for 5 days) did not change sucrose preference. Transcriptomic profiling revealed substantial acute but transient changes in the PFC: at 3 h post-injection there were roughly 400 upregulated and 1,155 downregulated transcripts in the PFC, including genes linked to neuronal plasticity and metabolism such as neuroplastin (Nptn), brain-derived neurotrophic factor (Bdnf), and Negr1; reactome enrichment included glycolysis and gluconeogenesis pathways. No persistent transcriptional differences in the PFC were observed at 4 weeks. The hypothalamic transcriptome showed no significant changes at either 3 h or 4 weeks. During RNA-seq QC, two samples with almost no reads and one enriched for wound-healing/immune genes were excluded from analysis. Across the in vivo experiments the authors report no apparent adverse effects of the psilocybin regimens used.

The investigators interpret their findings as evidence that, in these mouse models and with the regimens tested, psilocybin does not produce meaningful reductions in food intake or body weight nor does it improve binge-like eating. Despite a clear acute molecular signature in the PFC and a reduction in sucrose preference after a single high dose, the absence of durable transcriptional changes in the PFC and of effects in the hypothalamus led the authors to conclude that peripheral administration of psilocybin did not induce the homeostatic or behavioural changes necessary to lower body weight in the models studied. The authors situate these null results against earlier work showing psilocybin and other serotonergic agonists can modulate feeding and plasticity, noting that psilocybin is a 5-HT2A agonist and a weak 5-HT2C agonist and that serotoninergic pathways are implicated in human BMI and surgical weight loss. They highlight that transcriptional and plasticity effects were strong and rapid in the PFC but did not endure and were absent in the hypothalamus, which may help explain the lack of metabolic impact. Fadahunsi and colleagues also acknowledge that rodent models may not capture aspects of psychedelic action that are important in humans, such as the subjective, context-dependent, and psychotherapeutic components that accompany clinical psychedelic-assisted interventions. Key limitations noted by the authors include the translational uncertainty of rodent paradigms for psychedelic mechanisms, the fact that all experiments were performed once, and that peripheral administration and the dosing schedules employed may not replicate the human therapeutic context in which psychedelic-assisted psychotherapy is delivered. They nevertheless point to the reduced sucrose preference and acute cortical plasticity as signals that psilocybin could modulate reward valuation and might be worth investigating in targeted human subpopulations or as part of a combined therapeutic package (psychedelic treatment plus psychotherapy and lifestyle modification). The authors recommend further study — particularly clinical evaluation — before ruling out psilocybin for disordered eating or weight-management indications, while noting that their preclinical data do not support broad use of psilocybin as a metabolic or anti-obesity agent.