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

This animal study (2022) explored the effects of psilocybin and metformin (a drug used to manage blood sugar) in a rat model of obesity. In the low – not medium – and high dose psilocybin groups, a significant decrease in body weight was observed compared to controls. The metformin (type 2 diabetes medicine) group produced a greater decrease in body weight than either psilocybin group or the control. The medium dose psilocybin group was terminated from the study as they were incorrectly treated with the drug.

Abstract

“Background: There are currently relatively few effective pharmacological treatments for obesity, and existing ones may be associated with limiting side-effects. In the search for novel anti-obesity agents, drugs that modify central serotonergic systems have historically proven to be effective in promoting weight loss. Psilocin, which is rapidly metabolized from psilocybin, is an agonist at multiple serotonin receptors. In the present study we assessed the effects of psilocybin and a positive control (metformin) on changes in body weight in a rat model of obesity.

Methods: Five groups of adult male rats were pre-conditioned with a cafeteria diet until obese (>600 g) and then treated with either psilocybin (0.1, 1, or 5 mg/kg, i.p.), metformin (300 mg/kg, p.o.) or vehicle control. Treatments were for 27 consecutive weekdays, and body weights and high calorie food intake were recorded daily. Fasting glucose levels were recorded after 11 days of treatment. At the end of treatment rats completed a glucose tolerance test, and multiple fat pads were dissected out to assess adiposity.

Results: The medium dose psilocybin group had to be terminated from the study prematurely. Both the low and high dose psilocybin groups caused a significant decrease in changes in body weight compared to controls. The metformin group produced a greater decrease in change in body weight than either psilocybin groups or controls. Both high dose psilocybin and metformin decreased consumption of the high calorie diet, and exhibited decreased central adiposity.

Conclusion: Psilocybin demonstrated modest but significant effects on weight gain. Further study is recommended.”

Authors: Joyce Huang, Michelle Pham, William J. Panenka, William G. Honer & Alasdair M. Barr

Summary

INTRODUCTION

Pharmacological treatments for obesity exert their therapeutic effects on a diverse range of physiological targets, including the central serotonergic system. However, the use of serotonin-related drugs has been associated with a number of serious side-effects, which has led to a focus on a more targeted approach using receptor-specific ligands.

The serotonin system remains a promising substrate for developing new anti-obesity medications, and the prodrug psilocybin has been used extensively by humans for religious and recreational purposes. It is unclear whether serotonergic psychedelics have weight modulating properties, but the mechanism underlying these observations remains to be understood.

We used a rodent model of obesity to examine the effects of chronic treatment with psilocybin on weight gain. We used two common doses of the drug as well as a “microdose” (0.1 mg/kg).

Animals

Ninety male, adult Sprague-Dawley rats were obtained from Charles River and were given a high calorie diet for 27 days. The rats were treated daily Monday – Friday, and were familiarized to handlers through being weighed every Monday, Wednesday, and Friday for at least 30 days prior to drug treatment. Animals were monitored for signs of general health on a daily basis, and all experimental procedures were approved by the University of British Columbia’s Animal Care and Use Committee.

Pharmaceutical Agents and Solutions

Three doses of psilocybin dissolved in sterile saline were used: low (0.1 mg/kg), medium (1.0 mg/kg), and high (5.0 mg/kg). Psilocybin was administered by IP injection rather than oral gavage due to the dearth of published studies on oral administration of the drug.

Cafeteria Diet

The highly palatable high-fat and high-sugar diet was composed of 10.9% crushed cheddar crackers, 53% chocolate hazelnut spread and 36% smooth peanut butter, and was mashed into a coarse paste. The mini-marshmallows were not dissolved into the paste.

Blood Collection and Intraperitoneal Glucose Tolerance Test

Glucose levels were measured before, after 10 or 11 days of treatment, and at the end of the study. An intraperitoneal glucose tolerance test was performed at the end of the study.

Statistical Analysis

Longitudinal data were analyzed using repeated-measures analysis of variance (ANOVA), and associations between variables were determined using Pearson correlation coefficient. Post-hoc tests were performed using the Fisher’s LSD test.

RESULTS

Rats were fed a cafeteria diet for 51 days to get them to the desired weight. The cafeteria-fed rats had a greater mean weight than the standard chow-only rats.

When relative weight gain was analyzed, the control group exhibited the greatest relative weight gain, followed by the low dose psilocybin group, the high dose psilocybin group, and the metformin group. The low dose psilocybin group exhibited the least relative weight gain.

The repeated measures ANOVA indicated a non-significant main effect of drug treatment and a significant drug by time interaction. The metformin and high dose psilocybin groups ate less food than the control animals over the entire treatment period, but the high calorie diet control group consumed more food than all other groups from days 1 – 6, and significantly more than the high dose psilocybin and metformin groups from days 7 – 13.

The control group consumed the most calories, followed by the low dose psilocybin group, the high dose psilocybin group, and then the metformin group. The metformin group consumed significantly fewer calories than the vehicle control group.

Analysis of fasting glucose levels did not indicate a significant main effect of group, but a modest increase in fasting glucose levels was observed in high calorie diet animals.

The normal diet group exhibited lower glucose levels than all of the other groups, particularly at the 1 h time point, and a return to baseline levels by 2 h.

The weights of different fad pads at the end of treatment showed significant group differences for two of the three fat regions. The normal diet group had lower relative adiposity than the high calorie fed group.

Subcutaneous and retroperitoneal fat weights were significantly correlated with glucose intolerance, but not perirenal fat. Total relative weight gain was significantly correlated with total amount of high calorie diet consumed.

DISCUSSION

In this study, chronic treatment with psilocybin or metformin resulted in decreased body weight in a rat model of obesity. Psilocybin and metformin caused lower relative central adiposity than the high calorie diet-fed control group, but no effect on fasting glucose levels or glucose sensitivity in the IGTT.

These findings suggest that psilocybin may have modest weight-loss properties, which could feasibly extend to humans. However, the current model species, laboratory rats, will typically continue to gain weight throughout their lifetime. Psilocybin treated rats showed a slowed rate of weight gain, which could correspond to a weight-loss in humans. However, the drug was only able to slow weight gain, rather than cause absolute weight-loss.

The significantly greater effect of metformin on change in body weight than the two doses of psilocybin may indicate that the weight-altering effects of the latter drug are less effective, although uncertainties exist around equivalent dosing between the two drugs and their relative weight-altering effects in humans.

Psilocybin doses of 0.1, 1, and 5 mg/kg equate to 0.016, 0.16, and 0.81 mg/kg in humans, respectively. It is also possible that the 5 mg/dose of psilocybin represents a higher dose than is typically used in humans.

We did not observe any effect of drug treatment on glucose levels in the high calorie diet animals, perhaps because the effects of the diet were modest and the statistical power of drug treatment was limited by the small effect size.

We studied the effects of psilocybin on rats with obesity and metabolic syndrome/diabetes. The rats did not develop frank diabetes, but the animals did demonstrate more pronounced glucose dysregulation in the GTT.

In the high calorie diet rats, the effects of psilocybin were not as strong as those of metformin, and it is possible that the low dose psilocybin group selectively reduced their consumption of the less palatable regular chow rather than the high calorie diet. Psilocybin, a psychoactive drug, is rapidly dephosphorylated in the body to the active metabolite psilocin, which is an agonist at 5-HT1A, 5-HT2A, and 5-HT2C receptors with moderate-to-high affinity. Psilocin may also reduce feeding through other mechanisms, including suppressing conditioned responding and impulsivity.

The effects of psilocybin on obesity have now been observed twice in our laboratory, and further studies are presently addressing these possibilities. However, we are not able to provide any insight into the molecular mechanisms involved in decreased weight gain. This study used repeated, chronic treatment with psilocybin, whereas most human trials typically use a much small number of doses, often in combination with psychotherapy. Further studies with higher doses of the drug may be necessary to make further advances in this area. The present study provides preliminary findings that repeated exposure to psychedelic drugs can result in behavioral tolerance and downregulation of the 5-HT2A receptor.

From a rodent model of obesity, psilocybin has potential weight reducing properties, which are relatively fast onset. Psilocybin may have value as a weight-loss tool, whereby it could be consumed orally and therefore on a more frequent basis, even if weight loss effects were only modest.