All Traditional CB1 Receptor Blockers Caused Anxiety-Like Side Effects in Rats, and "Next-Gen" Alternatives Performed Poorly | Research

The takeaway

In a head-to-head comparison, all five classical CB1 antagonists reduced weight in obese rats but also caused anxiety, while four non-traditional alternatives (partial agonists, neutral antagonists, peripherally restricted compounds) either caused convulsions or lacked any activity.

Readers interested in why CB1 receptor-based weight loss drugs have not reached the market.

All 5 classical CB1 blockers caused anxiety; all 4 "safer" alternatives either caused convulsions or had no effect

What the researchers found

Researchers conducted the first direct comparison of classical and next-generation CB1 receptor blockers for anti-obesity potential and psychiatric side effects.

All five classical CB1 antagonists (rimonabant, taranabant, otenabant, ibipinabant, surinabant) effectively reduced body weight and food intake in obese rats in a body weight-dependent manner, with only slight effects on metabolic syndrome markers. However, all five also increased ultrasonic vocalizations (a measure of anxiety/distress in rats), confirming that the psychiatric side effects are a class effect, not specific to rimonabant.

The non-traditional alternatives fared poorly: the partial agonist O-1269 and the neutral antagonist LH-21 caused convulsive behavior at effective doses. The neutral antagonist VCHSR and the peripherally restricted inverse agonist JD-5037 showed no activity at the doses tested.

Why it matters

The withdrawal of rimonabant from the obesity market raised hopes that alternative CB1 blockers could achieve weight loss without psychiatric side effects. This study dashes those hopes for the specific compounds tested, showing that the alternatives either shared the problems or lacked efficacy. The endocannabinoid system remains a tantalizing but elusive target for obesity treatment.

The numbers in context

5 classical CB1 blockers tested: rimonabant, taranabant, otenabant, ibipinabant, surinabant. 4 non-traditional alternatives: O-1269, VCHSR, LH-21, JD-5037. All classical blockers reduced weight but increased anxiety. O-1269 and LH-21: convulsions. VCHSR and JD-5037: no activity.

How the study worked

In vivo screening cascade in rats: potency testing (CB1 agonist-induced hypothermia reversal, fasting-induced food intake), diet-induced obesity model with metabolic markers, and anxiety assessment via ultrasonic vocalization testing.

What this study cannot tell us

Rat study that may not predict human responses. Only one dose or limited dose range was tested for some compounds. The non-traditional compounds may have performed better at different doses or with different formulations. Ultrasonic vocalizations as a measure of anxiety may not perfectly correspond to human psychiatric side effects.

How to read the evidence

Preliminary evidence from a single animal study, though with comprehensive head-to-head comparison.

When this study was published

Published in 2017. CB1 antagonist development for obesity continues to be challenging.

The bigger picture

This study represents a reality check for the CB1 antagonist field. The anxiety side effects appear to be inherent to blocking CB1 in the brain, and the alternative compounds tested so far have not solved the problem. Future approaches may need to focus on tissue-selective or peripherally restricted strategies, but the currently available tools are inadequate.

Questions still open

Will truly peripherally restricted CB1 blockers eventually prove effective and safe? Are there allosteric CB1 modulators that could reduce appetite without the full blockade that causes anxiety? Should the field abandon central CB1 antagonism entirely for obesity?

Common questions

Why can't we use CB1 blockers for weight loss?

The problem is the endocannabinoid system in the brain: blocking CB1 receptors reduces appetite and weight, but also causes anxiety and depression because the same receptors regulate mood. This study showed every classical CB1 blocker caused anxiety, and the alternatives designed to avoid this either caused seizures or did not work at all.

Could cannabis-based approaches help with weight management?

Paradoxically, despite THC causing "the munchies" acutely, some epidemiological data suggests cannabis users have lower obesity rates. This study examined the opposite approach: blocking CB1 to reduce appetite. The challenge remains separating the metabolic benefits from the mood effects of targeting this system.

Read the original research

Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo.

Pharmacology, biochemistry, and behavior, 159, 24-35

View on PubMed ↗Publisher’s paper ↗

Citation

Varga, Balázs; Kassai, Ferenc; Szabó, György; Kovács, Péter; Fischer, János; Gyertyán, István. (2017). Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo.. Pharmacology, biochemistry, and behavior, 159, 24-35. https://doi.org/10.1016/j.pbb.2017.06.012