Can Psilocybin Treat Obesity? New Evidence, Future Directions

Empty Calories: Medication Options for the Obesity Epidemic
Obesity is a worldwide health concern – the World Health Organization reports 39% of adults globally are overweight, and 13% are considered obese.1 While the cause of obesity is still debated,2–4 medical professionals agree that the condition is a multifaceted health disorder with contributing genetic, psychological, and environmental factors leading to consequential secondary health concerns.5–7

Medications that address this widespread health concern are few and far between. While newer drugs such as semaglutide and tirzepatide which mimic specific hormones are promising approaches to weight loss,8 there arDetailse few drugs presently approved for this primary use. Historically, treatment tactics have ranged from prescription amphetamines (that come along with a high risk of dependence and addiction) to amphetamine-like drugs, which stimulate norepinephrine release (such as phentermine).9,10 These drugs, however, can result in serious and undesirable side effects and have a high risk of abuse – thus, they are now rarely prescribed for obesity and weight-loss indications.

Details
The mid-century development of the serotonergic (5-HT) agonist fenfluramine showed promise as an effective obesity treatment.10 Preclinical investigations identified that fenfluramine acts as an agonist at 5-HT1B and 5-HT2C receptors,11 with 5-HT2C activation thought to give rise to its appetite-suppressing effects.9,12 Clinically, fenfluramine can induce cardiac side effects and was linked with the development of valvular heart disease following chronic 5-HT2B activation.13 Thus, fenfluramine is no longer used as a treatment for obesity. However, the importance of 5-HT receptors in food-related behaviors and appetite suppression has reemerged as a point of interest in psychedelic research. Serotonergic psychedelics may be desirable drug targets for obesity treatment without the undesirable side effects and risk of developing valvular heart disease.

Psilocybin as a Novel Obesity Treatment
A new preclinical study from Alasdair M. Barr’s laboratory at the University of British Columbia investigated the effects of psilocybin on high-fat diet food consumption and weight gain.14 This study (funded by Neonmind Biosciences) used a male rat model of obesity to determine the efficacy of psilocybin (at 0.1 mg/kg, 1.0 mg/kg, and 5 mg/kg doses) to reduce high-fat, high-sugar “cafeteria diet” food consumption and body weight (Figure 1). Psilocybin was compared with a positive control drug metformin, which is commonly prescribed to overweight patients with prediabetes or type 2 diabetes and regulates the body’s insulin secretion, subsequently reducing sugar (glucose) levels in the blood.

Prior to beginning the drug treatment regimen, blood tests were taken to measure baseline glucose levels. 27 days of drug treatment (psilocybin or metformin) were combined with daily body weight and food intake tracking, as well as another blood test to measure glucose levels halfway through treatment (day 10-11). After drug treatments were completed, a glucose tolerance test was performed. This test is a commonly used method of determining how consumed glucose is metabolized by the body through measuring circulating levels at various time points post-consumption. Additionally, dissection of fat pads was performed at the end of the study for analysis of fat tissue and to determine if psilocybin or metformin treatments had any effect on tissue volume and specific tissue types.
Here

FIGURE 1. STUDY TIMELINE ILLUSTRATING FLOW OF THE EXPERIMENTAL PROTOCOL USED FOR INVESTIGATING PSILOCYBIN’S POTENTIAL FOR OBESITY TREATMENT. MALE RATS WERE FED A HIGH-FAT DIET UNTIL WEIGHTS REACHED THE DESIRED TARGET OF ~600 GRAMS, FOLLOWED WITH BLOOD COLLECTION TO MEASURE CIRCULATING GLUCOSE LEVELS. DRUG TREATMENT WITH PSILOCYBIN (0.1 MG/KG, 1.0 MG/KG [EXCLUDED DUE TO EXPERIMENTAL ERROR], AND 5.0 MG/KG) OR METFORMIN (300 MG/KG) OR CONTROL SALINE INJECTIONS COMMENCED FOR 27 DAYS, WITH DAILY WEIGHT AND FOOD INTAKE TRACKING AND ANOTHER BLOOD SAMPLE OF GLUCOSE LEVELS AT 10-11 DAYS INTO TREATMENT. AFTER 27 DAYS, RATS UNDERWENT GLUCOSE TOLERANCE TESTING, WITH INJECTIONS OF GLUCOSE AND BLOOD SAMPLING AT MULTIPLE TIMEPOINTS. THE EXPERIMENT FINISHED WITH DISSECTION AND COLLECTION OF ADIPOSE TISSUE. ADAPTED FROM HUANG ET AL. 2022 BY JULIET MECCIA, CREATED WITH BIORENDER.COM.Details

The 1.0 mg/kg psilocybin group was excluded due to drug administration error, leaving the low-dose (0.1 mg/kg) and high-dose (5.0 mg/kg) psilocybin treatment groups for final analysis. The sizeable difference in drug dose between these two groups coupled with the current precedent in preclinical research to use 1.0 mg/kg of psilocybin as an effective dose leaves a gap in our ability to interpret how a typical dose of psilocybin may alter weight gain and high-fat food consumption.15,16
Male rats fed the high-calorie cafeteria diet and who received saline injections showed the highest rate of weight gain, with an average of ~6% body weight change compared with their starting weight. By comparison, control rats fed a normal laboratory diet and receiving saline injections only had an average ~4% increase in body weight compared with their baseline. Compared to animals receiving non-drug injections of saline, both psilocybin doses were efficacious at decreasing weight-gain in rats fed a cafeteria diet – the groups given 0.1 mg/kg and 5.0 mg/kg of psilocybin respectively showed averages of ~5% and ~4.5% body weight changes, compared to their starting weights. Rats fed a high-calorie diet and treated with metformin exhibited the greatest changes in relative body weight, with an average ~3% change.Details

Due to the formulation of the high-calorie diet, it was not possible to determine whether animals treated with psilocybin or metformin showed preference towards specific macronutrients – this would prove an interesting follow-up, and would contribute to our understanding of how pharmacologically different treatments for obesity may alter food-intake behavior in regards to specific types of nutrients (for example, fats versus sugars).

Leave a Reply

Your email address will not be published. Required fields are marked *